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WO2023208165A1 - Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical application thereof - Google Patents

Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical application thereof Download PDF

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Publication number
WO2023208165A1
WO2023208165A1 PCT/CN2023/091444 CN2023091444W WO2023208165A1 WO 2023208165 A1 WO2023208165 A1 WO 2023208165A1 CN 2023091444 W CN2023091444 W CN 2023091444W WO 2023208165 A1 WO2023208165 A1 WO 2023208165A1
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Prior art keywords
alkyl
substituted
membered
group
ring
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PCT/CN2023/091444
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French (fr)
Chinese (zh)
Inventor
张晨
廖雨亭
徐进雄
余彦
唐平明
邹思佳
陈孝刚
高秋
程新帆
李宇鹏
李瑶
严庞科
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四川海思科制药有限公司
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Publication of WO2023208165A1 publication Critical patent/WO2023208165A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in AR-related diseases such as cancer diseases.
  • Androgen receptor is a hormone nuclear receptor that can be structurally divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD), which can regulate the induction of Gene expression in prostate cancer, therefore, inhibition of the androgen receptor is an effective approach to treating prostate cancer.
  • the androgen receptor inhibitors currently on the market such as enzalutamide and bicalutamide, mainly exert inhibitory effects by interacting with the ligand-binding domain (LTD) of the androgen receptor, but some patients may experience symptoms during treatment.
  • Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer. How to solve the problem of resistance has become a focus of clinical medicine.
  • Small molecule degraders are drugs that use the body's ubiquitin-proteasome system (UPS) to perform targeted degradation of target proteins. With its unique catalytic mechanism, small molecule degraders can target difficult-to-drug targets and solve the problem of drug resistance. They are currently a hot topic in the field of drug research and development such as tumors and autoimmune diseases.
  • UPS ubiquitin-proteasome system
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases Such compounds can be recognized by the proteasome of cells, causing the degradation of targeted proteins, and can effectively reduce the target protein. The protein content in cells.
  • Molecular glue is a type of small molecule that brings the target protein into contact with E3 ubiquitin ligase, inducing interaction between the two, thereby leading to the degradation of the target protein. From a functional perspective, molecular glue mainly works by filling the gap between the target protein and E3 ubiquitin ligase, enhancing the binding interface between the two and promoting a strong interaction between the two (Nat. Commun., 2022, 13, 815). Compared with traditional small molecule inhibitors, molecular glues have the advantages of catalytically driving target protein degradation and not requiring a binding pocket on the target protein, and have the potential to act on undruggable targets.
  • the purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, safer, and capable of inhibiting and degrading AR or/and AR-Vs (especially AR-V7) for the treatment of AR and AR.
  • Related diseases such as prostate cancer.
  • the present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
  • L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
  • L is selected from a bond or -C 1-20 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
  • L is selected from a bond or -C 1-10 hydrocarbyl-, 1 to 10 of the hydrocarbyl groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 )
  • the methylene unit is optionally replaced by -Ak-, -Cy-; in certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4 or Ak5;
  • each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
  • each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the optionally substituted groups: 4-7 membered heteromonocycle, 4-10 membered heterocycle, 5 -12-membered heterospirocycle, 7-10-membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group , benzo C 4-6 carbocyclyl, benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, it is substituted by 1 to 4 R L2 , the heterocyclyl, heteroaryl, heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from
  • NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkoxy , substituted by a hydroxyl-substituted C 1-4 alkyl group or a C 1-4 alkoxy substituent, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-C
  • L is selected from the group consisting of -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2 -Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-
  • L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1 -Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Cy1-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3
  • L is selected from
  • L is selected from a bond or a group shown in Table L-1, and the left side of the group is connected to B;
  • L is selected from the groups shown in Table L-2, and the left side of the group is connected to B;
  • R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl,
  • the heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
  • each R L is independently selected from H or C 1-6 alkyl
  • each R L is independently selected from H or C 1-4 alkyl
  • each R L is independently H, methyl, or ethyl
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bond or optionally substituted following groups: 4-7 membered nitrogen-containing heteromonocycle, 4-10 membered nitrogen-containing heterocycle Paracyclic ring, 5-12-membered nitrogen-containing heterospirocycle, 7-10-membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, is 1 to 4 R L2 substitutions, the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups, substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl, azepinenyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, Furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazole Pyrimidine, pyrazopyridyl, pyrazopyrazinyl, pyrazopyrazin
  • each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the following groups, substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
  • Cy1, Cy2, and Cy3 are each independently selected from one of the following groups, substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
  • L is selected from
  • Cy1 is selected from 4-6 membered nitrogen-containing heterocycles
  • L is selected from
  • L is selected from -Cy1-Cy2-
  • Cy1 is selected from phenyl, naphthyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heterocyclyl Aryl, 8 to 10 membered ring heteroaryl
  • Cy2 is selected from 4 to 6 membered nitrogen-containing heterocycles, preferably azetidinyl, pyrrolidinyl or piperidinyl, the Cy1 or Cy2 is optionally substituted by 1 to Substituted by 4 substituents selected from R L2 ;
  • L is selected from The left side is directly connected to B, and Cy2 is selected from 4-6 membered nitrogen-containing heterocycles, preferably azetidinyl, pyrrolidinyl or piperidinyl;
  • rr is selected from 0, 1, 2, 3, or 4;
  • B is selected from
  • V is selected from
  • V is selected from
  • P 1 and P 2 are each independently selected from
  • each v 2 is independently selected from 0, 1, 2, 3, or 4;
  • each v 1 is independently selected from 0, 1, or 2;
  • v3 is selected from 0, 1, 2, or 3;
  • v 4 is selected from 0, 1, 2, or 3;
  • z is selected from 0, 1, 2, or 3;
  • B is selected from
  • B is selected from In certain embodiments, B is selected from
  • B is selected from R b6 is selected from -(CH 2 ) m1 -C 3-6 cycloalkyl
  • R b7 is selected from H, F, Cl, CN, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 ring Alkyl or -CH 2 -C 3-6 cycloalkyl, the alkyl, alkynyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN , substituted by a C 1-4 alkyl substituent;
  • B is selected from R b7 is preferably H, F, Cl, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, B 4 is preferably phenyl or 5- to 6-membered heteroaryl, and B 2 is preferably pyrazole, as described B 4 is optionally replaced by 1 to 4 R b1 , and the B 2 is optionally replaced by 1 to 4 R b2 ;
  • B is selected from B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and said B 1 is optionally substituted by 1 to 4 R b1 ; in certain embodiments, B is selected from B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;
  • B is selected from B 5 selected from 6-membered heteroaryl (such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl), 8 to 10-membered heteroaryl (such as quinolyl, isoquinolinyl, quinazolinyl), B 1 is preferably benzene group or a 5 to 6-membered heteroaryl group, the B 1 is optionally substituted by 1 to 4 R b1 , and the B 5 is optionally substituted by 1 to 4 R b2 ;
  • 6-membered heteroaryl such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl
  • 8 to 10-membered heteroaryl such as quinolyl, isoquinolinyl, quinazolinyl
  • B 1 is preferably benzene group or a 5 to 6-membered heteroaryl group, the B 1 is optionally substituted by 1 to 4 R
  • B is selected from B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;
  • B is selected from y1 is selected from 0, 1, 2 or 3;
  • B is selected from
  • B is selected from
  • B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from
  • B is selected from
  • W is selected from O or S;
  • W is selected from O;
  • Ring S is selected from 4 to 9 membered nitrogen-containing heterocyclyl groups, and Ring S is optionally substituted by 1 to 4 Rs ;
  • Ring S is selected from a 5-, 6-, or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;
  • Ring S is selected from azepanyl, azepanyl, and Ring S is optionally substituted by 1 to 4 Rs ;
  • B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and the B 1 is optionally substituted by 1 to 4 R b 1 , and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl, and said B 1 and B 4 are optionally represented by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10- 14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
  • B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridine base, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolinyl, 3-isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-Tetrahydroquinolyl, benzofuryl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl ,
  • the B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;
  • B1 is selected from substituted or unsubstituted phenyl or pyridyl, and when substituted, is optionally substituted by 1 to 4 Rb1 ;
  • B1 is selected from y1 is selected from 0, 1, 2 or 3;
  • B1 is selected from Ba is selected from N, CR b1 , Bb is selected from N, CR b1 , Bc is selected from N, CR b1 , Bd is selected from N, CR b1 , and at most 2 of Ba, Bb, Bc and Bd are N, R b1A Selected from C 3-6 cycloalkyl, C 2-6 alkynyl, phenyl or 5 to 6-membered heteroaryl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl , phenyl, pyrazolyl, the cycloalkyl, alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, phenyl, heteroaryl, pyrazolyl C
  • B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and the B 2 is optionally substituted by 1 to 4 R b 2 , and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 , said B 2 is optionally substituted by 1 to 4 R b 2 , and said heterocyclyl
  • the base contains 1 to 4 heteroatoms selected from O, S, and N;
  • B2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5-10 membered heterobridged ring,
  • the B 2 is optionally substituted by 1 to 4 R b2 , and the heteroaryl, heterocyclyl, heterocycle, and heterobridged ring contain 1 to 4 heteroatoms selected from O, S, and N;
  • B2 is selected from 5-7 membered heterocyclyl, 5-6 membered heteroaryl, or 9-10 membered heterocyclic ring, and B2 is optionally substituted by 1 to 4 R b2 ,
  • the heteroaryl group, heterocyclic group, and heterocyclic ring contain 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from B 5 ;
  • B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazole base, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4-Tetrahydroquinolyl, 1,2,3,4- Tetrahydroisoquinolinyl, or B5 , when substituted, by 1 to 4 R b2 ;
  • B2 is selected from pyrazolyl, and B2 is optionally substituted by 1 to 4 R b2 ;
  • B 2 is selected from pyrazolyl, and said B 2 is substituted by 1 R b2a , optionally substituted by 1 to 3 R b2 ;
  • B2 is selected from The right side is directly connected to L;
  • B2 is selected from The right side is directly connected to L;
  • B 3 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R b1 , said The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridge Carbocyclyl, 4-7-membered monocyclic heterocyclyl, 7-14-membered heterocyclic ring, 7-14-membered heterospirocyclic ring, the B 3 is optionally substituted by 1 to 4 R b1 , the hetero Aryl, heterocyclyl, heterocyclic and heterospirocyclic rings contain 1 to 4 heteroatoms selected from O, S and N;
  • B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzimidazole base, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzopyrrolidinyl, benzopiperidinyl, chromanyl, 3-pyridazinonyl, 2-pyridine Keto group, 1,2,3,4-tetrahydroquinolyl group, 1,2,3,4-tetrahydroisoquinolyl group, pyridimidazolyl group, pyridopyrrolyl group, carbazolyl group, 2,3- Indolyl, benzomorpholinyl, When substituted, by 1 to 4 R b1 ;
  • B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, benzopyridyl, benzothienyl, benzofuranyl, Thienyl, furyl, pyrrolyl, when substituted, are substituted by 1 to 4 R b1 ;
  • B 4 is selected from phenyl, 5-6 membered heteroaryl, the phenyl or heteroaryl is optionally substituted by 1 to 4 R b1 , the heteroaryl contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 4 is selected from one of the following groups: phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, substituted or unsubstituted. When replaced, it is replaced by 1 to 4 R b1 ;
  • B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and said B 4 is substituted by 1 R b1a , optionally replaced by 1 to 3 R b1 ;
  • B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and said B 4 is substituted by 1 R b1a , optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • B 4 is selected from phenyl and pyridyl, and the B 4 is substituted by 1 R b1a , optionally substituted by 1 to 3 R b1 ;
  • B5 is selected from C 12-18 tricyclic, 12 to 18 membered heterotricyclic, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl , pyrazinyl, triazinyl, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, Triazolo C 4-6 carbocyclic ring, triazolo C 4-6 carbocyclic ring, imidazo C 4-6 carbocyclic ring, imidazo C 4-6 carbocyclic ring, thieno C 4-6 carbocyclic ring, thiophene And 4 to 6 membered heterocycle, furo C 4-6 carbocyclic ring, furo 4 to 6 membered heterocycle
  • B 5 selected from The B 5 is optionally substituted by 1 to 4 R b2 ;
  • R b1 is selected from F, Cl, CN, CF 3 , -OCF 3 , methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclo Butyl or R b1a ;
  • R b1 is selected from R b1a ;
  • R b2 is selected from R b2a ;
  • R b21 is each independently selected from H, methyl, ethyl, isopropyl;
  • R b22 is each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
  • n is each independently selected from 0, 1, 2, 3, or 4;
  • n is each independently selected from 0, 1, and 2;
  • n is each independently selected from 0, 1;
  • R b3 , R b4 , R b6 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 - R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio group, C 3-12 cycloalkyl group, C 6-10 aryl group, 5-10 membered heteroaryl group or 3-12 membered heterocyclyl group, the alkyl group, alkenyl group or alkynyl group , alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 deuterium, F, Cl, Br, I
  • R b3 and R b4 are not H at the same time;
  • R b6 and R b7 are not H at the same time;
  • R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8-membered heteromonocyclic ring
  • the cycloalkyl group or heteromonocyclic ring is optionally replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl , the heteromonocyclic, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • R b3 and R b4 are each independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3- 6 cycloalkyl) or 3 to 8 heteromonocyclic rings, the alkyl, alkynyl, cycloalkyl or heteromonocyclic ring is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C Substituted with 2-4 alkynyl or 3 to 8 heterocyclyl substituents, the heteromonocyclic and heterocyclic groups contain 1 to 4 heteroatoms selected from O, S, and N;
  • R b3 and R b4 are each independently selected from H, OH, NH 2 or optionally substituted one of the following groups: methyl, ethyl, ethynyl, propynyl, propargyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl,
  • R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group) or a 3 to 8-membered heteromonocyclic ring.
  • the alkyl or heteromonocyclic ring is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano Substituted with C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 carbocyclyl or 3 to 8 heterocyclyl substituents, the heteromono The ring contains 1 to 4 heteroatoms selected from O, S, and N;
  • R b3 and R b4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxy Heterocyclylbutyl, oxolyl, oxanyl, cyclobutylspirocyclobutyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH , NH 2 , N(CH 3 ), CN, CF 3 , CHF 2 ,
  • R b3 and R b5a , R b1 and R b5a are directly connected to form ring S, ring S is selected from 4 to 9 membered nitrogen-containing heterocyclyl groups, and ring S is optionally surrounded by 1 to 4 members selected from R Substituted by s substituent;
  • each R s is independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy base, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally replaced by 1 Substituted with 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy, the heterocyclyl or heteroaryl Contains 1 to 4 heteroatoms selected from O, S, and N;
  • each R s is independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, Substituted by I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents;
  • each R s is independently selected from ⁇ F, Cl, Br, I, OH, NH 2 , CN, methyl, ethyl, methoxy, ethoxy or cyclopropyl;
  • R b5a is selected from H or R b5 ;
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl base, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, cycloalkyl group, aromatic group
  • the base, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-6
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl group , cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted by 1 to 4 C selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen Substituents of 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 hetero
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl group, 5-6 membered heteroaryl group, 4-8 membered heterocyclyl group, 5-10 membered heterobridged ring, 5-12 membered heterospiro ring, 5-12 membered heteroacyclic ring, the alkyne
  • the base, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring is optionally 1 to 4 selected from
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 Or one of the following groups, substituted or unsubstituted: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, Pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclopropylcyclopropyl, cyclopropyl Cyclobutyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl,
  • R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3 -12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, Aryl, heteroaryl or heterocyclyl are optionally substituted with 1 to 4 C 1-4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, and hal
  • heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3 -6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4- 8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocycle, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkyl
  • R b3 , R b4 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 - R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, Ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-Diazepanyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobuty
  • each X is independently selected from NH, O, or S;
  • X is each independently selected from NH, O;
  • each R b24 is independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl,
  • each R b24 is independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl,
  • the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • each m1 is independently selected from 0, 1, 2, or 3;
  • each m2 is independently selected from 0, 1, 2, or 3;
  • m2 is each independently selected from 0, 1, and 2;
  • R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , methyl, ethyl, ethynyl, propynyl, Propargyl, -CH 2 -cyclopropyl , -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxo Heterocyclopentyl, -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O-cyclobutyl, -CH 2 O - cyclopropyl, -CH 2 OCH 2
  • R b7 is selected from one of the following groups, substituted or unsubstituted: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, morpholine, phenyl, thiophene base, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocycle Butyl, cyclopropyl,
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 or optionally substituted one of the following groups: ethynyl, propynyl, propargyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxanyl , -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O-cyclobutyl, -CH 2 O-cyclopropyl, -CH 2 OCH 2 -cyclobutyl, -CH 2 OCH 2 -cyclopropyl, -
  • R b6 is selected from C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, or -CH 2 CH 2 -C 3-8 cycloalkyl, said cycloalkyl
  • the group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl
  • Selected from B 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the B 1 is substituted by 1 R b1a , optionally substituted by 1 to 3 R b1 , and B 2 is selected from 5-10 A membered heterocyclic group, the B 2 is optionally substituted by 1 to 3 R b2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • Selected from B 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the B 1 is optionally substituted by 1 to 4 R b1 , B 2 is selected from the 5-10 membered heterocyclyl, the B 2 is substituted by 1 R b2a , optionally substituted by 1 to 3 R b2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • Selected from Selected from or C 5-10 spirocycle as described Substituted by 1 to 3 selected from R b3a , the spiro ring is optionally substituted by 1 to 3 selected from halogen or R b3a ;
  • B1 is selected from phenyl substituted with 3 to 5 R b1 ;
  • R b3a is each independently selected from OH, NH 2 , CN, N(C 1-4 alkyl) 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl or C 1-4 alkoxy substituents;
  • each R b3a is independently selected from OH, NH 2 , CN, N(CH 3 ) 2 , CF 3 , -CH 2 CN, methyl, ethyl, methoxy or ethoxy. Substituted by substituents;
  • R b1a is selected from -C 1-4 alkylene-(C ⁇ C)-H, -C 1-4 alkylene-NH 2 , -C 1-4 alkylene-N (C 1-4 alkyl) 2 , -C 1-4 alkylene-NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 5-6 cycloalkyl, C 5-9 spiro Ring, 5 to 6-membered heteroaryl, -(C ⁇ C)-CH 3 , cyclopropyl, cyclobutyl, Phenyl, the -(C ⁇ C)-CH 3 is 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl or C 3-6 cycl
  • R b1a is selected from -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 2 NH 2 , -(C ⁇ C)-CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazole base, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, Phenyl, the -(C ⁇ C)-CH 3 is 1 to 3 selected from F, Cl, Br, I,
  • R b1a is selected from -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 2 NH 2 ,
  • R b2a is selected from -COOH, -CONH 2 , -(CH 2 ) n -NH 2 , -(CH 2 ) n -N(C 1-4 alkyl) 2 , -(CH 2 ) n -NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -(CH 2 ) n -OH, -(CH 2 ) n -C 2-4 alkynyl, -(CH 2 ) n OC 1-4 alkyl, -(CH 2 ) n O(CH 2 ) n OC 1-4 alkyl, -(CH 2 ) n -O(CH 2 ) n OC 3-6 cycloalkyl, -C 1 -4 alkylene - 4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, the alkylene, alkyl, cycloalkyl, heterocycly
  • R b2a is selected from -COOH, -CONH 2 , -CH 2 NH 2 , C(CH 3 ) 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 2 O-cyclopropyl, -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , phenyl,
  • B is not
  • B is selected from one of the structural fragments shown in Table B-1:
  • B is selected from one of the structures shown in Table B-2;
  • each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • each q is independently selected from 0, 1, 2, 3, or 4;
  • each q is independently selected from 0, 1, or 2;
  • n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • p1 or p2 are each independently selected from 0, 1, 2, or 3;
  • p1 or p2 are each independently selected from 0, 1 or 2;
  • K is selected from K1, K2, K3, K4;
  • K1 is selected from
  • K1 is selected from
  • K2 is selected from
  • K2 is selected from
  • K3 is selected from
  • K3 is selected from
  • K4 is selected from In certain embodiments, K4 is selected from
  • each E is independently selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 3-12 membered heterocyclic ring, or a 5-12 membered heteroaromatic ring.
  • each E is independently selected from a C 3-10 carbocyclic ring, a benzene ring, a 4-12 membered heterocyclic ring, a 5-12 membered heteroaromatic ring, and the heterocyclic or heteroaromatic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • E is each independently selected from a benzene ring, a 5-6 membered heteroaromatic ring, and the heterocyclic ring or heteroaromatic ring contains 1 to 3 (e.g., 1, 2, 3) selected from O, Heteroatoms of S and N;
  • E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring, oxane ring Azole ring, indoline ring, isoindoline ring, 1,2,3,4-tetrahydroquinoline ring or 1,2,3,4-tetrahydroisoquinoline ring;
  • each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxane ring.
  • azole ring ;
  • E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring;
  • each E is independently selected from a benzene ring or a pyridine ring;
  • A is selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 3-10 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring containing 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • A is selected from a C 3-8 carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • A is selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;
  • A is selected from a benzene ring or a pyridine ring
  • each F is independently selected from a C 3-20 carbocyclic ring, a C 6-20 aromatic ring, a 3-20 membered heterocyclic ring, or a 5-20 membered heteroaromatic ring,
  • the heterocyclic or heteroaromatic ring contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • each F is independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 branched carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4 -7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14 aryl group, 5-10 Metaheteroaryl,
  • the heteromonocyclic ring, heteroparacyclic ring, heterospirocyclic ring, heterobridged ring or heteroaromatic ring contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • each F is independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 branched carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4 -7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14 aryl group, 5-10 Metaheteroaryl,
  • the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
  • each F is independently selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring,
  • each F is independently selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring,
  • each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopentyl[c]pyridyl , 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, Pyridinidazolyl, benzimidazolyl, benzo
  • Q is each independently selected from bond, -O-, -S-, -CH2- , -NRq- , -CO-, -NRqCO- , -CONRq- , or 3- 12-membered heterocycle
  • Q is each independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -, or 4-7
  • the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, 4) heterocycles selected from O, S, N atom;
  • R q is selected from H or C 1-6 alkyl
  • R q is selected from H or C 1-4 alkyl
  • R q is selected from H, methyl, ethyl
  • each R k2 is independently selected from bond, -CO-, -SO 2 -, -SO-, or -C(R k3 ) 2 -;
  • each R k2 is independently selected from -CO-, -SO 2 -, or -C(R k3 ) 2 -;
  • Rk1 is selected from Rk7a ;
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • two R k3 and the carbon atom or ring skeleton directly connected to the two together form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring
  • two R k3 and the carbon atom or ring skeleton directly connected to the two together form a C 3-6 carbocyclic ring or 3-7 membered heterocyclic ring
  • each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so
  • each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
  • each R k5 is independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
  • each R k5 is independently selected from CO, CH 2 , SO 2 or
  • each R k6 is independently selected from CO, CH, SO, SO 2 , CH 2 or N;
  • each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
  • each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
  • each Rk7 is independently selected from CO, CH, N, CH2 , O, S, N( CH3 ), or NH;
  • each Rk7 is independently selected from CH2 , O, N( CH3 ), or NH;
  • R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1 Substituted by -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl substituents;
  • R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1 Substituted by -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
  • R k7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, Substituted with substituents of CN, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
  • Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, the methyl, ethyl, propyl base, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl 1 to 4 are selected from F, Cl, Br
  • R k7a is selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH(CH 3 )-cyclopropyl, -CH 2 -cyclopropyl , -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2 CH 2 -methoxy;
  • R k7a is selected from H, CF 3 , methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;
  • R k7a is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl
  • each Rk8 is independently selected from C, N, or CH;
  • each R k9 is independently selected from bond, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
  • each R k9 is independently selected from CO, SO 2 or CH 2 ;
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • M 3 is selected from -NH- or -O-;
  • G is selected from a C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring
  • K is selected from one of the structural fragments shown in Table K-1:
  • K is selected from one of the structural fragments shown in Table K-2;
  • K is selected from one of the structural fragments shown in Table K-3:
  • K is selected from
  • L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
  • R L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
  • Each -Cy- is independently selected from a bond or one of the optionally substituted groups: 4-8 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterospirocyclic ring Heterobridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl group, Benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, heteroaryl,
  • the heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N.
  • B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl.
  • the B 1 is optionally substituted by 1 to 4 R b1 .
  • the heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
  • B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl.
  • the B 2 is optionally substituted by 1 to 4 R b2 .
  • the heterocyclyl contains 1 to 4 selected from O, Heteroatoms of S and N;
  • V is selected from
  • W is selected from O or S
  • P 1 and P 2 are each independently selected from
  • v 2 are each independently selected from 0, 1, 2, 3 or 4;
  • v 1 are each independently selected from 0, 1 or 2;
  • heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
  • n is independently selected from 0, 1, 2, 3 or 4;
  • R b3 , R b4 , R b6 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio
  • the base, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 ,
  • R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring.
  • the cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms.
  • ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • R b3 and R b5a , R b1 and R b5a are directly connected to form ring S.
  • Ring S is selected from 4 to 9-membered nitrogen-containing heterocyclic groups. Ring S is optionally substituted by 1 to 4 substituents selected from Rs . replaced;
  • R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 F , Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group or heteroaryl group contains 1 to 4 options Heteroatoms from O, S, N;
  • R b5a is selected from H or R b5 ;
  • X is each independently selected from NH, O or S;
  • n1 is each independently selected from 0, 1, 2 or 3;
  • n2 is independently selected from 0, 1, 2 or 3;
  • R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl,
  • the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • R b24 are each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl.
  • K is selected from K1, K2, K3, K4;
  • Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 3-12 membered heterocycles,
  • R q is selected from H or C 1-6 alkyl
  • A is selected from C 3-10 carbocyclic ring, C 6-10 aromatic ring, 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring.
  • the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or heteroatoms of N;
  • Each F is independently selected from C 3-20 carbocyclic ring, C 6-20 aromatic ring, 3-20 membered heterocyclic ring or 5-20 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from Heteroatom of O, S or N;
  • R k2 is each independently selected from bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
  • Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
  • R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl
  • M 3 is selected from -NH- or -O-;
  • the heteroaromatic ring contains 1 to 4 heteroatoms selected from N, O or S;
  • n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
  • v 2 are each independently selected from 1, 2, 3 or 4;
  • v 1 are each independently selected from 0, 1 or 2;
  • v 3 is selected from 0, 1, 2 or 3;
  • v 4 is selected from 0, 1, 2 or 3;
  • z is selected from 0, 1, 2 or 3;
  • W is selected from O or S
  • B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl.
  • the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , and the heterocyclic
  • the base contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 .
  • the B 2 is optionally substituted by 1 to 4 R b2 , and the heterocyclyl contains 1 to 4 optional R b 2 .
  • B 3 is selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl.
  • the B 3 is optionally substituted by 1 to 4 R b1 .
  • the heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
  • B 5 is selected from C 12-18 tricyclic ring, 12 to 18 membered heterotricyclic ring, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine base, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, triazolo C 4- 6 carbocyclic ring, triazolo 4 to 6 membered heterocyclic ring, imidazo C 4 to 6 carbocyclic ring, imidazo 4 to 6 membered heterocyclic ring, thieno C 4 to 6 carbocyclic ring, thieno 4 to 6 membered heterocyclic ring , furo C 4-6 carbocyclic ring, furo C
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl, cycloalkyl, aryl ,
  • the heteroaryl or heterocyclic group is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, and cyano.
  • heteroaryl Or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group or The heterocyclic group is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alky
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring.
  • the cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms.
  • ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • Ring S is selected from a 5-membered, 6-membered or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;
  • R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy group, C 3-6 cycloalkyl group, the alkyl group, alkoxy group or cycloalkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , Substituted by CN, C 1-4 alkyl or C 1-4 alkoxy substituents;
  • B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;
  • B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5-10 membered heterobridged ring, and the B 2 is optionally replaced by 1 to 4 R b2 substituted, and the heteroaryl, heterocyclyl, heterocyclic, and heterobridged rings contain 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 1-membered monocyclic heterocyclyl, 7-14-membered heterocyclic, 7-14-membered heterospirocyclic, the B 3 is optionally substituted by 1 to 4 R b1 , the heteroaryl, heterocyclyl, Heterocyclic rings and heterospirocyclic rings contain 1 to 4 heteroatoms selected from O, S, and N;
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5 -6-membered heteroaryl, 4-8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocyclic, 5-12-membered heterocyclic, the alkynyl, cycloalkyl, aromatic
  • the base, heteroaryl, heterocyclyl, heterobridged ring, heterospiro ring or heterocyclic ring is optionally selected from 1 to 4 F, Cl
  • R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5 -10-membered hetero-bridged ring, 5-12-membered heterospiro ring, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkylthio
  • R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring.
  • the cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms.
  • ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl,
  • the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the alkoxy, cycloalkyl
  • B is selected from When , R b3 and R b4 cannot be selected from H at the same time;
  • L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-,
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or optionally substituted following groups: 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, Heteroaryl, heteromonocycle, heteroparacycle, heterospirocycle or heterobridged ring contain 1 to 4 heteroatoms selected from O, S, N. When the heteroatoms are
  • R L are each independently selected from H or C 1-6 alkyl
  • A is selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring or 5-6 membered heteroaromatic ring.
  • the heterocyclic ring or heteroaromatic ring contains 1 to 4 heterocyclic rings selected from O, S or N. atom;
  • F is each independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 paracyclic carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 8-15 membered heterotriacyclic ring, 5-12 membered heterospirocyclic ring, 5-10 membered heterobridged ring, C 6-14 aryl group, 5-10 membered heteroaryl group,
  • the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
  • the ring is selected from aromatic rings or non-aromatic rings
  • Each E is independently selected from C 3-10 carbocyclic ring, benzene ring, 4-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N;
  • R q is selected from H or C 1-4 alkyl
  • R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;
  • R k5 are each independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
  • R k6 is each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
  • R k7 are each independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
  • Rk8 is each independently selected from C, N or CH;
  • R k9 are each independently selected from keys, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
  • R ka is selected from O, S or NH
  • Rk7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C Substituted with substituents of 2-4 alkenyl, C 2-4 alkynyl, and C 3-6 cycloalkyl;
  • R k14 selected from
  • p1 is selected from 0, 1, 2 or 3;
  • p2 is selected from 0, 1, 2 or 3;
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: 4-7-membered nitrogen-containing heteromonocycle, 4-10-membered nitrogen-containing heterocyclic ring, 5-12-membered Nitrogen-containing heterospirocycle, 7-10 membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group base, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, substituted by 1 to 4 R L2 , the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S,
  • R L are each independently selected from H or C 1-4 alkyl
  • E and A are each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;
  • F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridimidazolyl, benzo Imidazolyl, benzopyrazolyl, benzo
  • R ka is selected from O, S or NH
  • R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
  • Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I,
  • p1 or p2 are each independently selected from 0, 1 or 2;
  • R L is selected from H, methyl or ethyl
  • q is independently selected from 0, 1 or 2;
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrole base, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridyl , pyrazolopyrazinyl, pyrazopyrimidiny
  • B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, 3- Isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-tetrahydroquinolyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl,
  • the B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;
  • B 2 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl , benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4 -Tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, or B5 , when substituted, by 1 to 4 R b2 ;
  • B 5 selected from The B 5 is optionally substituted by 1 to 4 R b2 ;
  • B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, Benzopyridyl, benzothienyl, benzofuryl, thienyl, furyl, pyrrolyl, when substituted, are substituted by 1 to 4 R b1 ;
  • R b3 and R b4 are each independently selected from H, OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, cyclobutylspirocyclobutyl, when When substituted, it is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl Substituents of base, cyclohexyl, azetidinyl, pyr
  • R b3 , R b4 and the carbon atoms to which they are connected together form one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazyl Aldyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, are selected from 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , N(CH 3 ), CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C Substituted with 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl substitu
  • n is independently selected from 0 and 1;
  • R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or substituted or unsubstituted as follows One of the groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetamine Butyl, oxetanyl, pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclo Propylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cycl
  • R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, pyrrolidinyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, cyclopropyl cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl,
  • X is each independently selected from NH, O or S;
  • n2 is each independently selected from 0, 1 or 2;
  • K is selected from one of the structural fragments shown in Table K-1;
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
  • B is selected from one of the structural fragments shown in Table B-1 or Table B-2;
  • K is selected from one of the structural fragments shown in Table K-2;
  • L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2, in which the left side of the group is connected to B;
  • L is the same as any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention.
  • K is the same as any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention.
  • L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -C
  • L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-, -Cy1- Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Cy1-, -Ak1- Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-Ak4-;
  • Cy1, Cy2, and Cy3 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, by 1 to 4 R L2 ;
  • B and K are the same as any one of the second, third, fourth, fifth, sixth and seventh embodiments of the present invention.
  • L is selected from -Cy1-Cy2-;
  • Cy1 is selected from one of the following optionally substituted groups: phenyl, Said Cy1 is optionally replaced by 1 to 3 R L2 ;
  • Cy2 is selected from The Cy2 is optionally replaced by 1 to 2 R L2 ;
  • the present invention relates to a following compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.
  • the present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate the disease or condition being treated to some extent (e.g., inhibit or degrade AR or AR cleavage). One or more symptoms of mutant-related diseases such as prostate cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-
  • the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
  • a method for treating diseases in mammals comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable
  • the salt or co-crystal, the therapeutically effective amount is preferably 1-1500 mg, and the disease preferably inhibits or degrades AR or AR splicing mutant-related diseases (such as prostate cancer).
  • a method for treating diseases in mammals includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
  • the present invention relates to a kit, which may include a composition in a single dose or multiple dose form.
  • the kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or co-crystals of the compound of the present invention or its stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or
  • the amount of cocrystal is the same as in the pharmaceutical composition described above.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the above-mentioned pharmaceutical composition for the preparation of treatment and AR Or application in drugs for diseases related to the activity or expression of AR splicing mutants.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatments and Application in drugs that inhibit or degrade AR or AR splice mutant-related diseases.
  • the present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions. Selected from prostate cancer.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • Halogen means F, Cl, Br or I.
  • Halo-substituted means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted” is simply referred to as "halogenated.”
  • Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition.
  • Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Hydrocarbyl refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms.
  • the hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or
  • the heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, aza Cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidine base, oxazolidinyl, oxazinalkyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms
  • alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl
  • alkynyl refers to substituted or unsubstituted linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to in the main chain Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl base, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- Hexynyl, 1-methyl-1-p
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
  • Carbocyclyl or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Bicyclic or 10 to 15-membered tricyclic system the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” may be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Sexually substituted C, N, and S can be oxidized into various oxidation states.
  • the heterocyclyl group can be connected to a heteroatom or a carbon atom.
  • the heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclyl group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl
  • Spirocyclic or “spirocyclyl” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • Non-limiting examples include:
  • Spiro or “spiryl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include: "And ring” or "and ring group” can be monovalent, divalent, trivalent or tetravalent.
  • the "bridging ring” or “bridging ring base” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbocyclic ring refers to a “carbocyclic ring” in which the ring system only consists of carbon atoms.
  • Carbon bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • Heteromonocycle refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system.
  • Heterocycle refers to a "paracycle” containing heteroatoms.
  • Heterospirocycle refers to a “spirocycle” containing heteroatoms.
  • Heterobridged ring refers to a “bridged ring” containing heteroatoms.
  • Aryl or "aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring.
  • the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms.
  • the aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include benzene ring, naphthalene ring, "Aryl” or “aryl ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Non-limiting examples include
  • Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
  • Constant 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
  • Substituted by 0 to X substituents selected from means substituted by 0, 1, 2, 3...
  • substituted with 0 to 4 substituents selected from means substituted with 0, 1, 2, 3 or 4 substituents selected from...
  • substituted with 0 to 5 substituents selected from means substituted with 0, 1, 2, 3, 4 or 5 substituents selected from...
  • the heterobridged ring is optionally substituted by 1 to 4 substituents selected from F means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from F.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings.
  • “4-7 membered heteromonocyclic ring” refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings
  • “5-10-membered heterocyclic ring” refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
  • Alkyl optionally substituted by F means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
  • IC 50 is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc. company.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
  • HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
  • Dissolve 1b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min.
  • Dissolve 2b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), react at room temperature for 30min, add 1mol/L dilute hydrochloric acid dropwise to adjust the pH to 6.
  • Add 50 mL of ethyl acetate separate the layers, wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g).
  • Preparation method Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 ⁇ m filter membrane, and prepare a sample solution.
  • Mobile phase system supercritical carbon dioxide/mixed solvent of methanol and acetonitrile.
  • Mobile phase A supercritical CO 2
  • mobile phase B mixed solution of methanol and acetonitrile containing 0.05% diethylamine, column temperature: 35°C
  • Compound 3 uses compound 2c as raw material, and the chiral isomer 1 and chiral isomer 2 of compound 3 are obtained by referring to the synthesis method of Example 2.
  • Mobile phase A supercritical CO 2
  • mobile phase B mixed solution of methanol and acetonitrile containing 0.05% diethylamine, column temperature: 35°C
  • Dissolve 4b (1.4g, 4.37mmol) in 5mL ethanol, add lithium hydroxide monohydrate (0.70g, 16.68mmol) and 3mL water, and react at 40°C for 2h. Cool the reaction solution to room temperature, adjust the pH to 3 with 1mol/L dilute hydrochloric acid, extract with 30mL ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, dissolve the concentrate in 10mL DCM, add 1 -Chloro-N,N,2-trimethylpropenylamine (0.88g, 6.60mmol), after reacting at room temperature for 2 hours, add triethylamine (1.33g, 13.14mmol) and 3-chloro-4-aminotrifluorotoluene in sequence (1.11g, 5.68mmol), reacted at room temperature for 18h.
  • Dissolve 4c (0.30g, 0.64mmol) in 5mL DMF, and add the above crude intermediate 1 (0.26g), TEA (0.19g, 1.88mmol), CuI (24mg, 0.13mmol) and PdCl 2 (PPh 3 ) in sequence 2 (90 mg, 0.13 mmol), replaced with nitrogen three times, and reacted at 80°C for 18 hours.
  • methyl iodide (0.92 g, 6.48 mmol
  • Dissolve 5a (0.87g, 2.60mmol) in 8mL ethanol, add lithium hydroxide monohydrate (0.42g, 10.00mmol) and 4mL water, and react at 40°C for 2h. Cool the reaction solution to room temperature, adjust the pH to 3 with 1 mol/L dilute hydrochloric acid, extract with 40 mL ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and dissolve the concentrate in 8 mL DCM , add 1-chloro-N,N,2-trimethylpropenylamine (0.53g, 3.97mmol), react at room temperature for 2 hours, then add triethylamine (0.80g, 7.91mmol) and 3-chloro-4-amino Trifluorotoluene (0.67g, 3.43mmol), reacted at room temperature for 19h.
  • Dissolve 5b (0.32g, 0.66mmol) in 9mL DMF, and add the above crude intermediate 1 (0.27g), TEA (0.20g, 1.98mmol), CuI (24mg, 0.13mmol) and PdCl 2 (PPh 3 ) in sequence 2 (90 mg, 0.13 mmol), replaced with nitrogen three times, and reacted at 80°C for 18 hours.
  • Dissolve 6a (4.06g, 20.00mmol) and 4-iodopyrazole (4.27g, 22.00mmol) in 50 mL acetonitrile, add cesium carbonate (9.77g, 30.00mmol), and react at 80°C for 3 hours. Cool the reaction system to room temperature, filter, and concentrate the filtrate under reduced pressure. Add 80 mL THF and 20 mL water to the residue to dissolve, add lithium hydroxide monohydrate (0.98 g, 23.36 mmol), and react at room temperature for 0.5 h.
  • Dissolve 6b (0.20g, 0.43mmol) in 5mL DMF, and add the above crude intermediate 1 (0.16g), TEA (0.13g, 1.28mmol), CuI (0.008g, 0.042mmol) and PdCl 2 (PPh 3 ) 2 (0.030g, 0.043mmol), replaced with nitrogen three times, and reacted at 55°C for 1 hour.
  • Compound 8 was obtained by referring to Example 1 using compound 8a as a raw material.
  • Compound 9 was obtained by referring to Example 7 using compound 9a as a raw material.
  • Compound 10 was obtained by referring to Example 1 using compound 10a as a raw material.
  • Dissolve 16c (0.9g, 2.5mmol) in 15mL tetrahydrofuran, add 5mL water, cool to 0°C, add lithium hydroxide monohydrate (315mg, 7.51mmol), and react at room temperature for 2h. Adjust the pH of the reaction solution to 4 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (60 mL ⁇ 3), wash the organic phase with saturated aqueous sodium chloride solution (60 mL ⁇ 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Preparation method Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 ⁇ m filter membrane, and prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% TFA).
  • Gradient elution method Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 23 (0.05g).
  • Preparation method Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 ⁇ m filter membrane, and prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% TFA).
  • Gradient elution method Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 26 (0.08g).
  • the trifluoroacetate of compound 27 was prepared using compound 27e+23B as raw materials, with reference to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetate of compound 27.
  • Compound 30 was prepared by using 29b and 17B as raw materials and referring to Example 29 to obtain compound 30 (60 mg).
  • Dissolve 31b (0.11g, 0.60mmol) in 3mL THF, add 3mL 6mol/L hydrochloric acid, and react at room temperature for 2h.
  • reverse Add 10 mL of water to the reaction solution, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, extract with 20 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 31c (0.11g).
  • Compound 31 Compound 31 (5 mg) was obtained by referring to Example 22 using compound 31c as a raw material.
  • Step 5 Preparation of p-toluenesulfonate of 38f
  • the trifluoroacetic acid salt of compound 41 was prepared using compound 41b as raw material, referring to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and lyophilized to obtain the trifluoroacetic acid salt of compound 41. Salt (50mg).
  • the trifluoroacetic acid salt of compound 42 was prepared using compound 42b as the raw material, referring to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetic acid salt of compound 42. Salt (6mg).
  • Dissolve 47a (0.7g, 2.27mmol) (see WO2012074951 for synthesis method) in 10mL methanol, add an aqueous solution of lithium hydroxide monohydrate (0.29g, 6.91mmol) (5mL), and react at room temperature for 2h. Add 50 mL of water to the reaction system, adjust the pH to 2 with 1 mol/L hydrochloric acid, extract with ethyl acetate (50 mL ⁇ 3), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (0.7 g).
  • Preparation method Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 ⁇ m filter membrane, and prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% TFA).
  • Gradient elution method Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 47 (0.05g).

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Abstract

The present invention relates to a compound represented by general formula (I) or a stereoisomer, a deuterated product, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, an intermediate thereof, and use thereof in AR-related diseases such as cancer. B-L-K (I)

Description

一种含氮杂环衍生物及其组合物和药学上的应用A nitrogen-containing heterocyclic derivative, its composition and pharmaceutical application 技术领域Technical field
本发明涉及一种通式(I)的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在AR相关疾病如癌症疾病中的用途。The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in AR-related diseases such as cancer diseases.
背景技术Background technique
雄激素受体(Androgen receptor,AR)是一种激素核受体，结构上可划分为N-端活化区域(NTD)、DNA结合区域(DBD)和配体结合区域(LTD)，能够调节诱发前列腺癌的基因表达，因此，抑制雄激素受体是治疗前列腺癌的有效方法。目前上市的雄激素受体抑制剂如恩杂鲁胺、比卡鲁胺等主要是通过与雄激素受体的配体结合区域(LTD)作用发挥抑制效果，但部分患者在治疗过程中会出现由于LTD片段缺失的雄激素受体剪切突变体(Androgen receptor splice variants,AR-Vs)导致的耐药现象。临床前研究表明，雄激素受体剪切突变体能加快恩杂鲁胺耐药的前列腺癌进展，如何解决其耐药问题成为临床医学的关注点。Androgen receptor (AR) is a hormone nuclear receptor that can be structurally divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD), which can regulate the induction of Gene expression in prostate cancer, therefore, inhibition of the androgen receptor is an effective approach to treating prostate cancer. The androgen receptor inhibitors currently on the market, such as enzalutamide and bicalutamide, mainly exert inhibitory effects by interacting with the ligand-binding domain (LTD) of the androgen receptor, but some patients may experience symptoms during treatment. Resistance caused by Androgen receptor splice variants (AR-Vs) lacking the LTD fragment. Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer. How to solve the problem of resistance has become a focus of clinical medicine.
小分子降解剂是一种利用机体泛素-蛋白酶体系统(UPS)对靶蛋白进行定向降解的药物。小分子降解剂凭借独特的催化机制，可以靶向难以成药的靶点，解决药物耐药问题，目前在肿瘤、自身免疫性疾病等药物研发领域是一大热点。Small molecule degraders are drugs that use the body's ubiquitin-proteasome system (UPS) to perform targeted degradation of target proteins. With its unique catalytic mechanism, small molecule degraders can target difficult-to-drug targets and solve the problem of drug resistance. They are currently a hot topic in the field of drug research and development such as tumors and autoimmune diseases.
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of cells, causing the degradation of targeted proteins, and can effectively reduce the target protein. The protein content in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received widespread attention in recent years.
分子胶(molecular glue)是一类促使靶蛋白和和E3泛素连接酶接触，诱导两者之间产生相互作用，从而导致靶蛋白降解的小分子。从功能性的角度说，分子胶主要是通过填补靶蛋白和E3泛素连接酶的空隙，增强二者的结合界面促进两者之间发生强相互作用(Nat.Commun.,2022,13,815)。与传统的小分子抑制剂相比，分子胶具有催化形式驱动靶蛋白降解和无需在靶蛋白上有结合口袋的优点，具有作用于不可成药靶点的潜力。Molecular glue is a type of small molecule that brings the target protein into contact with E3 ubiquitin ligase, inducing interaction between the two, thereby leading to the degradation of the target protein. From a functional perspective, molecular glue mainly works by filling the gap between the target protein and E3 ubiquitin ligase, enhancing the binding interface between the two and promoting a strong interaction between the two (Nat. Commun., 2022, 13, 815). Compared with traditional small molecule inhibitors, molecular glues have the advantages of catalytically driving target protein degradation and not requiring a binding pocket on the target protein, and have the potential to act on undruggable targets.
因此，有必要开发新型的雄激素受体剪切突变体(Androgen receptor splice variants,AR-Vs，特别是AR-V7突变体)抑制剂和E3泛素连接酶的PROTAC或其它小分子降解剂药物，用于治疗与雄激素受体剪切突变体相关的肿瘤疾病。Therefore, it is necessary to develop new androgen receptor splice mutants (AR-Vs, especially AR-V7 mutants) inhibitors and PROTACs of E3 ubiquitin ligase or other small molecule degrader drugs. , for the treatment of neoplastic diseases associated with androgen receptor splice mutants.
发明内容Contents of the invention
本发明的目的在于提供一种结构新颖的、药效好、生物利用度高、更安全、能抑制并降解AR或/和AR-Vs(特别是AR-V7)的化合物，用于治疗与AR相关疾病如前列腺癌。The purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, safer, and capable of inhibiting and degrading AR or/and AR-Vs (especially AR-V7) for the treatment of AR and AR. Related diseases such as prostate cancer.
本发明提供一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物， The present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
B-L-K   (I)；B-L-K (I);
在某些实施方案中，L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
在某些实施方案中，L选自键或-C1-20烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-20 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
在某些实施方案中，L选自键或-C1-10烃基-，所述烃基中有1至10个(例如1、2、3、4、5、6、7、8、9或10)亚甲基单元任选被-Ak-、-Cy-替换；在某些实施方案中，每个-Ak-各自独立地选自Ak1、Ak2、Ak3、Ak4或Ak5；In certain embodiments, L is selected from a bond or -C 1-10 hydrocarbyl-, 1 to 10 of the hydrocarbyl groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ) The methylene unit is optionally replaced by -Ak-, -Cy-; in certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4 or Ak5;
在某些实施方案中，每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个(例如1或2个)选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；In certain embodiments, each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -NR L (CH 2 ) q C(＝O)-, -( CH 2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH =CH-, -Si(R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O) (R L )-, -S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- is optionally replaced by 1 to 2 ( For example, 1 or 2) selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl Substituted with substituents of C 1-6 alkyl groups substituted by cyano groups;
在某些实施方案中，每个-Cy-各自独立地选自Cy1、Cy2、Cy3、Cy4或Cy5；In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
在某些实施方案中，每个-Cy-各自独立地选自键或者任选取代的如下基团之一：4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被被1至4个RL2取代，所述的杂环基、杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, each -Cy- is independently selected from a bond or one of the optionally substituted groups: 4-8 membered heteromonocycle, 4-10 membered heterocycle, 5-12 membered heterocycle Spirocycle, 7-10 membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl, benzo 4 to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the Heterocyclyl, heteroaryl, heteromonocycle, heteroparacycle, heterospirocycle or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally 1 or 2 =O substitutions;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或者任选取代的如下基团之一：4-7元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代代，所述的杂环基、杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the optionally substituted groups: 4-7 membered heteromonocycle, 4-10 membered heterocycle, 5 -12-membered heterospirocycle, 7-10-membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group , benzo C 4-6 carbocyclyl, benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, it is substituted by 1 to 4 R L2 , the heterocyclyl, heteroaryl, heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S , optionally replaced by 1 or 2 =O;
在某些实施方案中，RL2各自独立地选自氘、F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene -OC 1-4 alkyl, - OC 1-4 alkylene-OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene -OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 3-10 carbocyclyl, -OC 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, - C 0-4 alkylene-4 to 10-membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen substituted Substituted with C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heterocyclic groups selected from O, S, N atom;
在某些实施方案中，RL2各自独立的选自氘、F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所 述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene-OC 1-2 alkyl, -OC 1-2 alkylene- OC 3-6 carbocyclyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene -C 3-6 carbocyclyl, -C 0-2 alkylene -C 3-6 carbocyclyl, -C 0-2 alkylene- 4 to 6 membered heterocyclyl, so The above-mentioned alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic or heterocyclic groups are optionally selected from 1 to 4 F, Cl, Br, I, OH, COOH, CN, NH 2. NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkoxy , substituted by a hydroxyl-substituted C 1-4 alkyl group or a C 1-4 alkoxy substituent, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，RL2各自独立地选自氘、F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、-OCHF2、-OCF3、甲基、甲氧基、＝O、羟甲基、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代；In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or optionally substituted One of the groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, - CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-Methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, is selected from 1 to 4 F, CHF 2 , CF 3 , -OCHF 2 , -OCF 3 , Methane Substituted with substituents of base, methoxy, =O, hydroxymethyl, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 ;
在某些实施方案中，RL2各自独立的选自氘、F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、-N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基；In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, -N(C 1-4 alkyl) 2. =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，RL2各自独立的选自氘、F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基；In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 Alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，RL2各自独立的选自氘、F、CF3、OH、甲基、甲氧基、＝O、羟甲基、COOH、NHCH3、N(CH3)2、CN或NH2；In certain embodiments, each R L2 is independently selected from deuterium, F, CF 3 , OH, methyl, methoxy, =O, hydroxymethyl, COOH, NHCH 3 , N(CH 3 ) 2 , CN or NH 2 ;
在某些实施方案中，L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；In certain embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3 -Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1 -Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5 -, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2 -Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3 -Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4 -, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4 -, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
在某些实施方案中，L选自键、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、 -Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；In certain embodiments, L is selected from the group consisting of -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2 -Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2 -Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2 -Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1 -Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2 -Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4 -Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
在某些实施方案中，L选自键、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-；In certain embodiments, L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1 -Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Cy1-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-Ak4-;
在某些实施方案中，L选自-Cy1-Cy2-，优选地，Cy1选自C6-10芳基、苯并C4-6碳环、苯并4至6元杂环、5至6元杂芳基或8至10元杂芳基，Cy2选自4至6元含氮杂环烷基、Cy2选自4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环，所述的杂环基、杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, L is selected from -Cy1-Cy2-, preferably, Cy1 is selected from C 6-10 aryl, benzo C 4-6 carbocycle, benzo 4 to 6 membered heterocycle, 5 to 6 4-membered heteroaryl or 8-10-membered heteroaryl, Cy2 is selected from 4-6-membered nitrogen-containing heterocycloalkyl, Cy2 is selected from 4-7-membered nitrogen-containing heteromonocyclic ring, 4-10-membered nitrogen-containing heterocyclic ring, 5-12 membered nitrogen-containing heterospirocycle, 7-10 membered nitrogen-containing heterobridged ring, the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 A heteroatom selected from O, S, N. When the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;
在某些实施方案中，L选自 In certain embodiments, L is selected from
在某些实施方案中，L选自键或表L-1所示的基团，基团左侧与B连接；In certain embodiments, L is selected from a bond or a group shown in Table L-1, and the left side of the group is connected to B;
在某些实施方案中，L选自表L-2所示的基团，基团左侧与B连接；In certain embodiments, L is selected from the groups shown in Table L-2, and the left side of the group is connected to B;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个(例如1或2个)选自卤素、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, - (CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -CH=CH-, -(C≡C) q -or bond, the -CH 2 -, -CH=CH- optionally substituted by 1 to 2 (eg 1 or 2) selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen Substituted with substituents of C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, and cyano-substituted C 1-4 alkyl;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、 -C(＝O)NH-或-NHC(＝O)-；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O- , -CH＝CH-, -CH＝C(CN)-, -CH＝C(F)-, -C(CN)＝CH-, -C(F)＝CH-, -C≡C-, - C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )- , -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C( =O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4各自独立的选自-C(＝O)-、-O-、NH、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-NHCO-；In certain embodiments, Ak1, Ak2, Ak3, Ak4 are each independently selected from -C(=O)-, -O-, NH, -CH=CH-, -CH=C(CN)-, -CH =C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -NHCO-;
在某些实施方案中，RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, The heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，RL各自独立的选自H或C1-6烷基；In certain embodiments, each R L is independently selected from H or C 1-6 alkyl;
在某些实施方案中，RL各自独立的选自H或C1-4烷基；In certain embodiments, each R L is independently selected from H or C 1-4 alkyl;
在某些实施方案中，RL各自独立的自H、甲基或乙基；In certain embodiments, each R L is independently H, methyl, or ethyl;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或者任选取代的如下基团之一：4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bond or optionally substituted following groups: 4-7 membered nitrogen-containing heteromonocycle, 4-10 membered nitrogen-containing heterocycle Paracyclic ring, 5-12-membered nitrogen-containing heterospirocycle, 7-10-membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, is 1 to 4 R L2 substitutions, the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡啶酮、三嗪基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶、吡唑并吡啶基、吡唑并吡嗪基、吡唑并嘧啶基、苯并噻吩基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、苯并吡咯基、三氮唑并吡啶基、三氮唑并嘧啶基、三氮唑并哒嗪基、三氮唑并吡嗪基、三氮唑并噻唑基、三氮唑并噁唑基、三氮唑并吡唑基、三氮唑并吡咯基、三氮唑并咪唑基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups, substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl, azepinenyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, Furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazole Pyrimidine, pyrazopyridyl, pyrazopyrazinyl, pyrazopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzo Pyrazolyl, benzopyrrolyl, triazolopyridyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiazyl, triazolo Oxazolyl, triazolopyrazolyl, triazolopyrrolyl, triazoloimidazolyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl , cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutyl Spirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidine base, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentyl Piperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, nitrogen Heterocyclobutylpiperidinyl, pyrrolidinaazetidinyl, pyrrolidinopyrrolidyl, pyrrolidinopiperidinyl, piperidinoazetidinyl, piperidinopyrrole Alkyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropyrolidinyl, cyclopentylspiroazetidinyl, cyclopentyl Spiropyrrolidinyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, azetidinylspiroazetidinyl, aza cyclobutylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazepine cyclobutyl, piperidylspiropiperidinyl, When substituted, by 1 to 4 R L2 ;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代；In certain embodiments, each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the following groups, substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
在某些实施方案中，Cy1、Cy2、Cy3各自独立的选自取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代；In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following groups, substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
在某些实施方案中，L选自 In certain embodiments, L is selected from
在某些实施方案中，Cy1选自4-12元含氮杂环，优选4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环，所述的含氮杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子，当杂原子选自S时，任选被0、1或2个＝O取代；In certain embodiments, Cy1 is selected from 4-12 membered nitrogen-containing heterocycles, preferably 4-7-membered nitrogen-containing heteromonocycles, 4-10-membered nitrogen-containing heterocyclic rings, 5-12-membered nitrogen-containing heterospirocycles, 7-10 membered nitrogen-containing heterocyclic bridge, the nitrogen-containing heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N, when the heteroatoms are selected from S , optionally replaced by 0, 1 or 2 =O;
在某些实施方案中，Cy1选自4-6元含氮杂环；In certain embodiments, Cy1 is selected from 4-6 membered nitrogen-containing heterocycles;
在某些实施方案中，L选自 In certain embodiments, L is selected from
在某些实施方案中，L选自-Cy1-Cy2-，Cy1选自苯基、萘基、苯并C4-6碳环基、苯并4至6元杂环基、5至6元杂芳基、8至10元并环杂芳基，Cy2选自4-6元含氮杂环，优选氮杂环丁基、吡咯烷基或哌啶基，所述Cy1或Cy2任选被1至4个选自RL2的取代基所取代；In certain embodiments, L is selected from -Cy1-Cy2-, Cy1 is selected from phenyl, naphthyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heterocyclyl Aryl, 8 to 10 membered ring heteroaryl, Cy2 is selected from 4 to 6 membered nitrogen-containing heterocycles, preferably azetidinyl, pyrrolidinyl or piperidinyl, the Cy1 or Cy2 is optionally substituted by 1 to Substituted by 4 substituents selected from R L2 ;
在某些实施方案中，L选自左侧与B直接连接，Cy2选自4-6元含氮杂环，优选氮杂环丁基、吡咯烷基或哌啶基；In certain embodiments, L is selected from The left side is directly connected to B, and Cy2 is selected from 4-6 membered nitrogen-containing heterocycles, preferably azetidinyl, pyrrolidinyl or piperidinyl;
在某些实施方案中，rr选自0、1、2、3或4；In certain embodiments, rr is selected from 0, 1, 2, 3, or 4;
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，V选自 In certain embodiments, V is selected from
在某些实施方案中，V选自 In certain embodiments, V is selected from
在某些实施方案中，V选自-N(Rb5a)C(＝W)-(CRb3Rb4)-、-C(＝W)-(CRb3Rb4)-、-C(＝W)-(CRb3Rb4)v2-、-(CRb3Rb4)C(＝W)(CRb3Rb4)-、-(CRb3Rb4)C(＝W)-、-N(Rb5a)C(＝W)N(Rb5a)-、-N(Rb5a)C(＝W)-、-N(Rb5a)C(＝W)-(CRb3Rb4)-N(Rb5a)-、-N(Rb5a)C(＝W)-(CRb3Rb4)-O-、-N(Rb5a)C(＝W)-(CRb3Rb4)2-N(Rb5a)-、-N(Rb5a)C(＝W)-(CRb3Rb4)2-O-、 -N(Rb5a)C(＝W)-(CRb3Rb4)2-N(Rb5a)C(＝W)-、-N(Rb5a)C(＝W)-(CRb3Rb4)-N(Rb5a)C(＝W)-、-NHC(＝W)-(CRb6Rb7)-、-C(＝W)-、-C(＝W)-C(＝W)-、-(CRb3Rb4)v1-N(Rb5a)C(＝W)-(CRb3Rb4)v2-、-N(Rb5a)C(＝W)-(CRb3Rb4)-C(＝W)-、-N(Rb5a)C(＝W)-C(＝W)-(CRb3Rb4)-、-N(Rb5a)C(＝W)-C(＝W)-、-C(＝W)-C(＝W)-、-C(＝W)-(CRb3Rb4)-C(＝W)-、-C(＝W)-N(Rb5a)-(CRb3Rb4)-、-C(＝W)-(CRb6Rb7)-C(＝W)-、-N(Rb5a)C(＝W)-C(＝W)-(CRb3Rb4)-、-N(Rb5a)C(＝W)-、-C(＝W)N(Rb5a)-、-N(Rb5a)C(＝W)N(Rb5a)-；In certain embodiments, V is selected from -N(R b5a )C(=W)-(CR b3 R b4 )-, -C(=W)-(CR b3 R b4 )-, -C(=W )-(CR b3 R b4 ) v2 -,-(CR b3 R b4 )C(＝W)(CR b3 R b4 )-,-(CR b3 R b4 )C(＝W)-,-N(R b5a )C(=W)N(R b5a )-, -N(R b5a )C(=W)-, -N(R b5a )C(=W)-(CR b3 R b4 )-N(R b5a ) -, -N(R b5a )C(=W)-(CR b3 R b4 )-O-, -N(R b5a )C(=W)-(CR b3 R b4 ) 2 -N(R b5a )- , -N(R b5a )C(=W)-(CR b3 R b4 ) 2 -O-, -N(R b5a )C(=W)-(CR b3 R b4 ) 2 -N(R b5a )C(=W)-, -N(R b5a )C(=W)-(CR b3 R b4 ) -N(R b5a )C(=W)-, -NHC(=W)-(CR b6 R b7 )-, -C(=W)-, -C(=W)-C(=W)-, -(CR b3 R b4 ) v1 -N(R b5a )C(=W)-(CR b3 R b4 ) v2 -, -N(R b5a )C(=W)-(CR b3 R b4 )-C( =W)-, -N(R b5a )C(=W)-C(=W)-(CR b3 R b4 )-, -N(R b5a )C(=W)-C(=W)-, -C(=W)-C(=W)-, -C(=W)-(CR b3 R b4 )-C(=W)-, -C(=W)-N(R b5a )-(CR b3 R b4 )-, -C(=W)-(CR b6 R b7 )-C(=W)-, -N(R b5a )C(=W)-C(=W)-(CR b3 R b4 )-, -N(R b5a )C(=W)-, -C(=W)N(R b5a )-, -N(R b5a )C(=W)N(R b5a )-;
在某些实施方案中，V选自-NH(C＝O)(CRb3Rb4)-、-NH(C＝O)(CRb6Rb7)-、-N(Rb5)(C＝O)(CRb3Rb4)-、-N(Rb5)(C＝O)(CRb6Rb7)-、-NH(C＝O)(CRb3Rb4)-NH-、-NH(C＝O)(CRb3Rb4)-O-、-NH(C＝O)(CRb3Rb4)-NH(C＝O)-、-NH(C＝O)(CRb3Rb4)-(C＝O)NH-、-NH(C＝O)(CRb3Rb4)-(C＝O)-、-NH(C＝O)-(C＝O)-、-NH(C＝O)-(C＝O)-、-(C＝O)-(C＝O)、-(C＝O)(CRb3Rb4)-、-NH(C＝O)-、-(C＝O)NH-、-NH(C＝O)NH-、-(C＝O)(CRb3Rb4)-、-NH(C＝O)(CRb3Rb4)-CH2-、-NH(C＝O)-CH2-(CRb3Rb4)-、-(C＝O)-；In certain embodiments, V is selected from -NH(C=O)(CR b3 R b4 )-, -NH(C=O)(CR b6 R b7 )-, -N(R b5 )(C=O )(CR b3 R b4 )-, -N(R b5 )(C＝O)(CR b6 R b7 )-, -NH(C＝O)(CR b3 R b4 )-NH-, -NH(C＝ O)(CR b3 R b4 )-O-, -NH(C＝O)(CR b3 R b4 )-NH(C＝O)-, -NH(C＝O)(CR b3 R b4 )-(C =O)NH-, -NH(C＝O)(CR b3 R b4 )-(C＝O)-, -NH(C＝O)-(C＝O)-, -NH(C＝O)- (C＝O)-, -(C＝O)-(C＝O), -(C＝O)(CR b3 R b4 )-, -NH(C＝O)-, -(C＝O)NH -, -NH(C＝O)NH-, -(C＝O)(CR b3 R b4 )-, -NH(C＝O)(CR b3 R b4 )-CH 2 -, -NH(C＝O )-CH 2 -(CR b3 R b4 )-, -(C＝O)-;
在某些实施方案中，Y1、Y2、Y3各自独立地选自键、O、S、NRb5a、C(＝S)、C(＝O)、CONRb5a、NRb5aCO；In certain embodiments, Y 1 , Y 2 , Y 3 are each independently selected from bond, O, S, NR b5a , C(=S), C(=O), CONR b5a , NR b5a CO;
在某些实施方案中，P1、P2各自独立地选自 In certain embodiments, P 1 and P 2 are each independently selected from
在某些实施方案中，v2各自独立地选自0、1、2、3或4；In certain embodiments, each v 2 is independently selected from 0, 1, 2, 3, or 4;
在某些实施方案中，v1各自独立地选自0、1或2；In certain embodiments, each v 1 is independently selected from 0, 1, or 2;
在某些实施方案中，v3选自0、1、2或3；In certain embodiments, v3 is selected from 0, 1, 2, or 3;
在某些实施方案中，v4选自0、1、2或3；In certain embodiments, v 4 is selected from 0, 1, 2, or 3;
在某些实施方案中，z选自0、1、2或3；In certain embodiments, z is selected from 0, 1, 2, or 3;
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自在某些实施方案中，B选自 In certain embodiments, B is selected from In certain embodiments, B is selected from
在某些实施方案中，B选自Rb6选自-(CH2)m1-C3-6环烷基，Rb7选自H、F、Cl、CN、C1-4烷基、C2-4炔基、C3-6环烷基或-CH2-C3-6环烷基，所述的烷基、炔基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基的取代基所取代；In certain embodiments, B is selected from R b6 is selected from -(CH 2 ) m1 -C 3-6 cycloalkyl, R b7 is selected from H, F, Cl, CN, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 ring Alkyl or -CH 2 -C 3-6 cycloalkyl, the alkyl, alkynyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN , substituted by a C 1-4 alkyl substituent;
在某些实施方案中，B选自Rb7优选H、F、Cl、甲基、乙基、环丙基、-CH2-环丙基，B4优选苯基或5至6元杂芳基，B2优选吡唑，所述的B4任选被1至4个Rb1所取代，所述的B2任选被1至4个Rb2所取代；In certain embodiments, B is selected from R b7 is preferably H, F, Cl, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, B 4 is preferably phenyl or 5- to 6-membered heteroaryl, and B 2 is preferably pyrazole, as described B 4 is optionally replaced by 1 to 4 R b1 , and the B 2 is optionally replaced by 1 to 4 R b2 ;
在某些实施方案中，B选自V选自-NHC(＝O)-、-NH(C＝O)(CRb3Rb4)-O-、 -NH(C＝O)(CRb3Rb4)-，B1优选苯基或5至6元杂芳基，所述的B1任选被1至4个Rb1所取代；In certain embodiments, B is selected from V is selected from -NHC(=O)-, -NH(C=O)(CR b3 R b4 )-O-, -NH(C=O)(CR b3 R b4 )-, B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;
在某些实施方案中，B选自B1优选苯基或5至6元杂芳基，所述的B1任选被1至4个Rb1所取代；在某些实施方案中，B选自B1优选苯基或5至6元杂芳基，所述的B1任选被1至4个Rb1所取代；In certain embodiments, B is selected from B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and said B 1 is optionally substituted by 1 to 4 R b1 ; in certain embodiments, B is selected from B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;
在某些实施方案中，B选自B5选自6元杂芳基(如吡啶基、吡嗪基、嘧啶基、哒嗪基)、8至10元杂芳基(如喹啉基、异喹啉基、喹唑啉基)，B1优选苯基或5至6元杂芳基，所述的B1任选被1至4个Rb1所取代，所述的B5任选被1至4个Rb2所取代；In certain embodiments, B is selected from B 5 selected from 6-membered heteroaryl (such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl), 8 to 10-membered heteroaryl (such as quinolyl, isoquinolinyl, quinazolinyl), B 1 is preferably benzene group or a 5 to 6-membered heteroaryl group, the B 1 is optionally substituted by 1 to 4 R b1 , and the B 5 is optionally substituted by 1 to 4 R b2 ;
在某些实施方案中，选自优选 In certain embodiments, Selected from preferred
在某些实施方案中，B选自B1优选苯基或5至6元杂芳基，所述的B1任选被1至4个Rb1所取代；In certain embodiments, B is selected from B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;
在某些实施方案中，B选自y1选自0、1、2或3；In certain embodiments, B is selected from y1 is selected from 0, 1, 2 or 3;
在某些实施方案中，B选自 (优选v1＝0或1,v2＝1)、 In certain embodiments, B is selected from (Preferably v1=0 or 1, v2=1),
的定义与B1相同； The definition of is the same as B 1 ;
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，选自 In certain embodiments, Selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自在某些实施方案中，B选自在某些实施方案中，B选自在某些实施方案中，B选自在某些实施方案中，B选自在某些实施方案中，B选自在某些实施方案中，B选自在某些实施方案中，B选自 In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from In certain embodiments, B is selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，W选自O或S；In certain embodiments, W is selected from O or S;
在某些实施方案中，W选自O；In certain embodiments, W is selected from O;
在某些实施方案中，环S选自4至9元含氮杂环基，环S任选被1至4个Rs取代；In certain embodiments, Ring S is selected from 4 to 9 membered nitrogen-containing heterocyclyl groups, and Ring S is optionally substituted by 1 to 4 Rs ;
在某些实施方案中，环S选自5元、6元或7元含有1或2个氮原子的环，环S任选被1至4个Rs取代；In certain embodiments, Ring S is selected from a 5-, 6-, or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;
在某些实施方案中，环S选自氮杂环戊基、氮杂环己基，环S任选被1至4个Rs取代；In certain embodiments, Ring S is selected from azepanyl, azepanyl, and Ring S is optionally substituted by 1 to 4 Rs ;
在某些实施方案中，B1选自C5-20碳环基或4-20元杂环基，所述B1任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and the B 1 is optionally substituted by 1 to 4 R b 1 , and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B1、B4各自独立的选自C6-14碳环基或4-14元杂环基，所述B1、B4任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl, and said B 1 and B 4 are optionally represented by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B1、B4各自独立的选自苯基、萘基、C6-12碳环基、5-10元杂芳基、5-10元杂环基、C10-14三环碳环基、12至14元三环杂环基，所述B1、B4任选被1至4个Rb1所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10- 14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
在某些实施方案中，B1、B4各自独立的选自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶 基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、3-异喹啉酮基、喹唑啉基、3,4-二氢-1H-苯并吡喃基、1,2,3,4-四氢喹啉基、苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、 所述B1、B4任选被1至4个Rb1所取代；In certain embodiments, B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridine base, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolinyl, 3-isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-Tetrahydroquinolyl, benzofuryl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl , The B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;
在某些实施方案中，B1选自取代或未取代的苯基或吡啶基，当被取代时，任选被1至4个Rb1所取代；In certain embodiments, B1 is selected from substituted or unsubstituted phenyl or pyridyl, and when substituted, is optionally substituted by 1 to 4 Rb1 ;
在某些实施方案中，B1选自y1选自0、1、2或3；In certain embodiments, B1 is selected from y1 is selected from 0, 1, 2 or 3;
在某些实施方案中，B1选自Ba选自N、CRb1，Bb选自N、CRb1，Bc选自N、CRb1，Bd选自N、CRb1，且Ba、Bb、Bc、Bd中至多有2个为N，Rb1A选自C3-6环烷基、C2-6炔基、苯基或5至6元杂芳基，优选环丙基、环丁基、环戊基、环己基、乙炔基、丙炔基、苯基、吡唑基，所述的环烷基、炔基、环丙基、环丁基、环戊基、环己基、乙炔基、丙炔基、苯基、杂芳基、吡唑基任选被1至4个选自F、Cl、Br、I、OH、＝O、-CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-OH、-C1-4亚烷基-O-C1-4烷基、C3-6环烷基的取代基所取代，优选地，任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、乙炔基、-CH2-CN、-CH2OH、-CH2OMe、-CH2-环丙基、甲氧基、环丙基、环丁基的取代基所取代；In certain embodiments, B1 is selected from Ba is selected from N, CR b1 , Bb is selected from N, CR b1 , Bc is selected from N, CR b1 , Bd is selected from N, CR b1 , and at most 2 of Ba, Bb, Bc and Bd are N, R b1A Selected from C 3-6 cycloalkyl, C 2-6 alkynyl, phenyl or 5 to 6-membered heteroaryl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl , phenyl, pyrazolyl, the cycloalkyl, alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, phenyl, heteroaryl, pyrazolyl C 1-4 alkyl optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen group, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene -OH, -C 1-4 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl substituents are substituted, preferably, optionally by 1 to 4 selected from F, Cl, Br, I, OH, CN , CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, - CH 2 -substituted with cyclopropyl, methoxy, cyclopropyl, cyclobutyl substituents;
在某些实施方案中，B2选自C5-20碳环基或4-20元杂环基，所述B2任选被1至4个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and the B 2 is optionally substituted by 1 to 4 R b 2 , and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自C5-10碳环基、5-10元杂环基或B5，所述B2任选被1至4个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 , said B 2 is optionally substituted by 1 to 4 R b 2 , and said heterocyclyl The base contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自C6-10芳基、5-7元杂环基、5-10元杂芳基或5-10元杂并环、5-10元杂桥环，所述B2任选被1至4个Rb2取代，所述的杂芳基、杂环基、杂并环、杂桥环含有1至4个选自O、S、N的杂原子；In certain embodiments, B2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5-10 membered heterobridged ring, The B 2 is optionally substituted by 1 to 4 R b2 , and the heteroaryl, heterocyclyl, heterocycle, and heterobridged ring contain 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自5-7元杂环基、5-6元杂芳基或9-10元杂并环，所述B2任选被1至4个Rb2取代，所述的杂芳基、杂环基、杂并环含有1至4个选自O、S、N的杂原子；In certain embodiments, B2 is selected from 5-7 membered heterocyclyl, 5-6 membered heteroaryl, or 9-10 membered heterocyclic ring, and B2 is optionally substituted by 1 to 4 R b2 , The heteroaryl group, heterocyclic group, and heterocyclic ring contain 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自B5；In certain embodiments, B 2 is selected from B 5 ;
在某些实施方案中，B2选自取代或未取代的如下基团之一：苯基、萘基、吡唑基、咪唑基、三氮唑基、噻唑基、噁唑基、异噁唑基、噻吩基、吡啶基、苯并吡咯基、苯并咪唑基、苯并吡唑基、苯并噻唑基、吡唑并四氢吡咯基、3-哒嗪酮基、2-吡啶酮基、1,2,3,4-四氢喹啉基、1,2,3,4- 四氢异喹啉基、 或B5，当被取代时，被1至4个Rb2取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazole base, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4-Tetrahydroquinolyl, 1,2,3,4- Tetrahydroisoquinolinyl, or B5 , when substituted, by 1 to 4 R b2 ;
在某些实施方案中，B2选自吡唑基，所述B2任选被1至4个Rb2取代；In certain embodiments, B2 is selected from pyrazolyl, and B2 is optionally substituted by 1 to 4 R b2 ;
在某些实施方案中，B2选自吡唑基，所述B2被1个Rb2a取代、任选被1至3个Rb2取代；In certain embodiments, B 2 is selected from pyrazolyl, and said B 2 is substituted by 1 R b2a , optionally substituted by 1 to 3 R b2 ;
在某些实施方案中，B2选自 右侧与L直接连接；In certain embodiments, B2 is selected from The right side is directly connected to L;
在某些实施方案中，B2选自右侧与L直接连接；In certain embodiments, B2 is selected from The right side is directly connected to L;
在某些实施方案中，B3选自C6-14碳环基或5-14元杂环基，所述碳环基或杂环基任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 3 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R b1 , said The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B3选自5-12元杂芳基、C6-7碳环基、C6-10并碳环基、C6-12螺碳环基、C7-12桥碳环基、4-7元单环杂环基、7-14元杂并环、7-14元杂螺环，所述B3任选被1至4个Rb1所取代，所述的杂芳基、杂环基、杂并环、杂螺环含有1至4个选自O、S、N的杂原子；In certain embodiments, B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridge Carbocyclyl, 4-7-membered monocyclic heterocyclyl, 7-14-membered heterocyclic ring, 7-14-membered heterospirocyclic ring, the B 3 is optionally substituted by 1 to 4 R b1 , the hetero Aryl, heterocyclyl, heterocyclic and heterospirocyclic rings contain 1 to 4 heteroatoms selected from O, S and N;
在某些实施方案中，B3选自取代或未取代的如下基团之一：苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并吡咯基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并三氮唑基、苯并吡咯烷基、苯并哌啶基、苯并四氢吡喃基、3-哒嗪酮基、2-吡啶酮基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、吡啶并咪唑基、吡啶并吡咯基、咔唑基、2,3-二氢吲哚基、苯并吗啉基、当被取代时，被1至4个Rb1取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzimidazole base, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzopyrrolidinyl, benzopiperidinyl, chromanyl, 3-pyridazinonyl, 2-pyridine Keto group, 1,2,3,4-tetrahydroquinolyl group, 1,2,3,4-tetrahydroisoquinolyl group, pyridimidazolyl group, pyridopyrrolyl group, carbazolyl group, 2,3- Indolyl, benzomorpholinyl, When substituted, by 1 to 4 R b1 ;
在某些实施方案中，B3选自取代或未取代的如下基团之一：苯基、萘基、 苯并吡啶基、苯并噻吩基、苯并呋喃基、噻吩基、呋喃基、吡咯基，当被取代时，被1至4个Rb1取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, benzopyridyl, benzothienyl, benzofuranyl, Thienyl, furyl, pyrrolyl, when substituted, are substituted by 1 to 4 R b1 ;
在某些实施方案中，B4选自苯基、5-6元杂芳基，所述苯基或杂芳基任选被1至4个Rb1所取代，所述的杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 4 is selected from phenyl, 5-6 membered heteroaryl, the phenyl or heteroaryl is optionally substituted by 1 to 4 R b1 , the heteroaryl contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B4选自取代或未取代的如下基团之一：苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，当被取代时，被1至4个Rb1所取代；In certain embodiments, B 4 is selected from one of the following groups: phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, substituted or unsubstituted. When replaced, it is replaced by 1 to 4 R b1 ;
在某些实施方案中，B4选自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，所述B4被1个Rb1a取代、任选被1至3个Rb1取代；In certain embodiments, B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and said B 4 is substituted by 1 R b1a , optionally replaced by 1 to 3 R b1 ;
在某些实施方案中，B4选自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，所述B4被1个Rb1a取代、任选被1至3个选自F、Cl、Br、I、OH、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In certain embodiments, B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and said B 4 is substituted by 1 R b1a , optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
在某些实施方案中，B4选自苯基、吡啶基，所述B4被1个Rb1a取代、任选被1至3个Rb1取代；In certain embodiments, B 4 is selected from phenyl and pyridyl, and the B 4 is substituted by 1 R b1a , optionally substituted by 1 to 3 R b1 ;
在某些实施方案中，B5选自C12-18三并环、12至18元杂三并环、噻吩基、呋喃基、噻唑基、噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、苯基、苯并C4-6碳环、苯并4至6元杂环、吡唑并C4-6碳环、吡唑并4至6元杂环、三氮唑并C4-6碳环、三氮唑并4至6元杂环、咪唑并C4-6碳环、咪唑并4至6元杂环、噻吩并C4-6碳环、噻吩并4至6元杂环、呋喃并C4-6碳环、呋喃并4至6元杂环、4-7元含氮杂单环烷基(例如氮杂环丁基、吡咯烷基、哌嗪基、哌啶基)、4-10元含氮杂并环烷基、5-12元含氮杂螺环烷基、7-10元含氮杂桥环烷基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基，所述B5任选被1至4个Rb2取代，所述的杂环、杂单环烷基、杂并环烷基、杂螺环烷基、杂桥环烷基含有1至4个选自O、S、N的杂原子；In certain embodiments, B5 is selected from C 12-18 tricyclic, 12 to 18 membered heterotricyclic, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl , pyrazinyl, triazinyl, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, Triazolo C 4-6 carbocyclic ring, triazolo C 4-6 carbocyclic ring, imidazo C 4-6 carbocyclic ring, imidazo C 4-6 carbocyclic ring, thieno C 4-6 carbocyclic ring, thiophene And 4 to 6 membered heterocycle, furo C 4-6 carbocyclic ring, furo 4 to 6 membered heterocycle, 4-7 membered nitrogen-containing heteromonocyclic alkyl (such as azetidinyl, pyrrolidinyl, pipera Azinyl, piperidinyl), 4-10-membered nitrogen-containing heterocycloalkyl, 5-12-membered nitrogen-containing heterospirocycloalkyl, 7-10-membered nitrogen-containing heterobridged cycloalkyl, 3-7-membered monocyclic ring Alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, the B 5 is optionally substituted by 1 to 4 R b2 , the heterocycle , heteromonocycloalkyl, heterocycloalkyl, heterospirocycloalkyl, and heterobridged cycloalkyl contain 1 to 4 heteroatoms selected from O, S, and N;
B5选自 所述B5任选被1至4个Rb2取代；B 5 selected from The B 5 is optionally substituted by 1 to 4 R b2 ;
在某些实施方案中，Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-ORb22、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-12环烷基(优选C3-6环烷基)、C6-10芳基、5-10元杂芳基(优选5-6元杂芳基)或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-OH、-C1-4亚烷基-O-C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -(CH 2 ) n -R b22 , -OR b22 , -N(R b21 ) 2 , -C(=O )N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S (=O) 2 N(R b21 ) 2 , -NR b21 C(=O)R b22 , -NR b21 S(=O) 2 R b22 , C 3-12 cycloalkyl (preferably C 3-6 cycloalkyl base), C 6-10 aryl group, 5-10 membered heteroaryl group (preferably 5-6 membered heteroaryl group) or 4-10 membered heterocyclic group, the -CH 2 -, alkyl group, alkenyl group, Alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N( R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkyne Base, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene -OH, -C 1-4 alkylene -OC 1-4 alkyl, C 3-6 Substituted with cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N ;
在某些实施方案中，Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3或者取代或未取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、环戊基并环戊基、吡咯烷基并吡咯烷基、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丁基螺环己基、环丁基螺哌啶基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、当被取代时，任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-2亚烷基-C3-6环烷基、-C1-2亚烷基-OH、-C1-2亚烷基-O-C1-4烷基、C3-6环烷基、5-6元杂芳基或4-6元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b1 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C(= O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2. -S(=O) 2 CH 3 or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, Piperidinyl, oxetanyl, oxolyl, oxanyl, morpholine, cyclopentacyclopentyl, pyrrolidinylpyrrolidinyl, pyrrolidinylcyclopentyl, aza Cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspiropiperidinyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspiro Cyclohexyl, cyclopentylspirocyclohexyl, When substituted, optionally by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , NHC 1-4 alkyl, N (C 1-4 alkyl) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-2 Alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, 5-6 Substituted with a substituent of a 4- to 6-membered heteroaryl group or a 4- to 6-membered heterocyclyl group, the heteroaryl group or heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、N(CH3)2、CN、 NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、乙炔基、-CH2-CN、-CH2OH、-CH2OMe、-CH2-环丙基、甲氧基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、咪唑基、吡唑基、三氮唑基、四氮唑基的取代基所取代；In certain embodiments, each R b1 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O ) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl , vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazole Base, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinyl Cyclopentyl, azetidinylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocycle Jiji, When substituted, 1 to 4 are selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, iso Propyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidine Substituted with substituents such as piperidinyl, morpholinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl;
在某些实施方案中，Rb1选自F、Cl、CN、CF3、-OCF3、甲基、乙基、甲氧基、乙氧基、乙炔基、丙炔基、环丙基、环丁基或Rb1a；In certain embodiments, R b1 is selected from F, Cl, CN, CF 3 , -OCF 3 , methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclo Butyl or R b1a ;
在某些实施方案中，Rb1选自Rb1a；In certain embodiments, R b1 is selected from R b1a ;
在某些实施方案中，Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4烷基、-C(＝O)N(C1-4烷基)2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-8环烷基、C6-10芳基、5至10元杂芳基、4至10元杂环基、-C1-4亚烷基-4至10元杂环基，所述的亚烷基、CH2、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基氧基、卤素取代的C3-6环烷基、卤素取代的C3-6环烷基氧基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C( =O)NH 2 , -C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -( CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, 4 to 10 membered heterocyclyl, -C 1-4 alkylene-4 to 10-membered heterocyclic group, the alkylene group, CH 2 , alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group are optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 Alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3-6 cycloalkyl Substituted with an oxygen group, a 5-6 membered heteroaryl group or a 4-8 membered heterocyclyl substituent, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4烷基、-C(＝O)N(C1-4烷基)2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-8环烷基、C6-10芳基、5至6元杂芳基、4至8元杂环基、-C1-4亚烷基-4至8元杂环基，所述的亚烷基、CH2、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、NH2、-NHC1-4烷基、-N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基氧基、卤素取代的C3-6环烷基、卤素取代的C3-6环烷基氧基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C( =O)NH 2 , -C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -( CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5 to 6-membered heteroaryl, 4 to 8-membered heterocyclyl, -C 1-4 alkylene-4 to 8-membered heterocyclic group, the alkylene group, CH 2 , alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group are optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1- 4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen substituted C 3-6 cycloalkyl substituted by a halogen-substituted C 3-6 cycloalkyloxy group, a 5-6-membered heteroaryl group or a 4-8-membered heterocyclyl substituent, and the heteroaryl group or heterocyclic group contains 1 to 4 A heteroatom selected from O, S, N;
在某些实施方案中，Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、NH(CH3)、N(CH3)2、CN、NO2、COOH、-C(＝O)NH2或者任选取代的如下基团之一：-CH2OCH2CH3、甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基，当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、甲氧基、乙氧基、吡唑基、吗啉基、氧杂环己基、环 丙基、环丁基、环丙基氧基、 的取代基所取代；In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 or optionally substituted one of the following groups: -CH 2 OCH 2 CH 3 , methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, alkyne Propyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Morpholinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, are selected from 1 to 4 F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxanyl, cyclohexyl propyl, cyclobutyl, cyclopropyloxy, Substituted by substituents;
在某些实施方案中，Rb2选自Rb2a；In certain embodiments, R b2 is selected from R b2a ;
在某些实施方案中，Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；In certain embodiments, R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, Substituted with substituents of NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;
在某些实施方案中，Rb21各自独立的选自H、甲基、乙基、异丙基；In certain embodiments, R b21 is each independently selected from H, methyl, ethyl, isopropyl;
在某些实施方案中，Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基、环烷基、烯基、炔基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C3-6环烷基氧基、C1-4烷氧基的取代基所取代；In certain embodiments, R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 ring Alkyl group, the alkyl group, alkoxy group, cycloalkyl group, alkenyl group, and alkynyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3. Substituted with substituents of COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, and C 1-4 alkoxy;
在某些实施方案中，Rb22各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基；In certain embodiments, R b22 is each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
在某些实施方案中，n各自独立的选自0、1、2、3或4；In certain embodiments, n is each independently selected from 0, 1, 2, 3, or 4;
在某些实施方案中，n各自独立的选自0、1、2；In certain embodiments, n is each independently selected from 0, 1, and 2;
在某些实施方案中，n各自独立的选自0、1；In certain embodiments, n is each independently selected from 0, 1;
在某些实施方案中，Rb3、Rb4、Rb6、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 , R b4 , R b6 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 - R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio group, C 3-12 cycloalkyl group, C 6-10 aryl group, 5-10 membered heteroaryl group or 3-12 membered heterocyclyl group, the alkyl group, alkenyl group or alkynyl group , alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or Substituted with 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
任选地，Rb3、Rb4不同时为H；Optionally, R b3 and R b4 are not H at the same time;
任选地，Rb6、Rb7不同时为H；Optionally, R b6 and R b7 are not H at the same time;
在某些实施方案中，Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8-membered heteromonocyclic ring, and the cycloalkyl group or heteromonocyclic ring is optionally replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl , the heteromonocyclic, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3、Rb4各自独立的选自H、OH、NH2、C1-4烷基、C2-4炔基、C3-8环烷基(优选C3-6环烷基)或3至8杂单环，所述的烷基、炔基、环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、C1-4烷氧基、C2-4炔基或3至8杂环基的取代基所取代，所述的杂单环、杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 and R b4 are each independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3- 6 cycloalkyl) or 3 to 8 heteromonocyclic rings, the alkyl, alkynyl, cycloalkyl or heteromonocyclic ring is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C Substituted with 2-4 alkynyl or 3 to 8 heterocyclyl substituents, the heteromonocyclic and heterocyclic groups contain 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3、Rb4各自独立的选自H、OH、NH2或者任选取代的如下基团之一：甲基、乙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯 烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基，当被取代时，被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、CF3、CHF2、甲基、甲氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、吡唑基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基的取代基所取代；；In certain embodiments, R b3 and R b4 are each independently selected from H, OH, NH 2 or optionally substituted one of the following groups: methyl, ethyl, ethynyl, propynyl, propargyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinyl Substituted with azolyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl substituents;;
在某些实施方案中，Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基(优选C3-6环烷基)或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8碳环基或3至8杂环基的取代基所取代，所述的杂单环含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group) or a 3 to 8-membered heteromonocyclic ring. The alkyl or heteromonocyclic ring is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano Substituted with C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 carbocyclyl or 3 to 8 heterocyclyl substituents, the heteromono The ring contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3、Rb4与其相连接的碳原子共同形成环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基，所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基任选被1至4个(例如1、2、3或4个)选自氘、F、Cl、Br、I、OH、NH2、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基或4至6杂环基的取代基所取代，所述的杂单环或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 and R b4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxy Heterocyclylbutyl, oxanyl, oxanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxa Cyclobutyl, oxanyl, and oxanyl are optionally selected from 1 to 4 (for example, 1, 2, 3 or 4) from deuterium, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl or Substituted with 4 to 6 heterocyclyl substituents, the heteromonocyclic or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3、Rb4与其相连接的碳原子共同形成环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基，所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、N(CH3)、CN、CF3、CHF2、甲基、乙基、异丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡唑基、噻唑基、三氮唑基、四氮唑基的取代基所取代；In certain embodiments, R b3 and R b4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxy Heterocyclylbutyl, oxolyl, oxanyl, cyclobutylspirocyclobutyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH , NH 2 , N(CH 3 ), CN, CF 3 , CHF 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, Substituted by substituents of cyclobutyl, azetidinyl, oxetanyl, pyrazolyl, thiazolyl, triazolyl, and tetrazolyl;
在某些实施方案中，Rb3与Rb5a、Rb1与Rb5a直接连接形成环S，环S选自4至9元含氮杂环基，环S任选被1至4个选自Rs的取代基所取代；In certain embodiments, R b3 and R b5a , R b1 and R b5a are directly connected to form ring S, ring S is selected from 4 to 9 membered nitrogen-containing heterocyclyl groups, and ring S is optionally surrounded by 1 to 4 members selected from R Substituted by s substituent;
在某些实施方案中，Rs各自独立的选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基、5-6元杂芳基或3至8杂环基，所述的烷基、烷氧基、环烷基、杂芳基或者杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R s is independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy base, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally replaced by 1 Substituted with 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy, the heterocyclyl or heteroaryl Contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rs各自独立的选自F、Cl、Br、I、OH、NH2、-NHC1-4烷基、-N(C1-4烷基)2、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基或者环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, each R s is independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, Substituted by I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents;
在某些实施方案中，Rs各自独立的选自\F、Cl、Br、I、OH、NH2、CN、甲基、乙基、甲氧基、乙氧基或环丙基；In certain embodiments, each R s is independently selected from \ F, Cl, Br, I, OH, NH 2 , CN, methyl, ethyl, methoxy, ethoxy or cyclopropyl;
在某些实施方案中，Rb5a选自H或Rb5；In certain embodiments, R b5a is selected from H or R b5 ;
在某些实施方案中，Rb5选自OH、NH2、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(= O)R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl are optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkane group, C 1-4 alkoxy group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 Substituted with a substituent of a heterocyclic group, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb5选自OH、NH2、甲基、乙基、丙基、异丙基、-(CH2)n-环丙基、-(CH2)n- 环丁基、-(CH2)n-环戊基、-(CH2)n-环己基、苯基、吡啶基，所述的-CH2-、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b5 is selected from OH, NH 2 , methyl, ethyl, propyl, isopropyl, -(CH 2 ) n -cyclopropyl, -(CH 2 ) n - Cyclobutyl, -(CH 2 ) n -cyclopentyl, -(CH 2 ) n -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally selected from 1 to 4 from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered hetero Substituted with a substituent of an aryl group or a 4-10 membered heterocyclyl group, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb5选自甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、苯基、吡啶基，所述的-CH2-、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；In certain embodiments, R b5 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 Substituted with substituents of alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl;
在某些实施方案中，Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl base, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, cycloalkyl group, aromatic group The base, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen, Substituted with cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclic The aryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4炔基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的炔基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl group , cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted by 1 to 4 C selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen Substituents of 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4炔基、C3-6环烷基、C5-10桥环烷基、C5-12螺环烷基、C4-12并环烷基、C6-10芳基、5-6元杂芳基、4-8元杂环基、5-10元杂桥环、5-12元杂螺环、5-12元杂并环，所述的炔基、环烷基、芳基、杂芳基、杂环基、杂桥环、杂螺环或杂并环任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基、杂环基、杂桥环、杂螺环或杂并环含有1至4个选自O、S、N的杂原子；In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl group, 5-6 membered heteroaryl group, 4-8 membered heterocyclyl group, 5-10 membered heterobridged ring, 5-12 membered heterospiro ring, 5-12 membered heteroacyclic ring, the alkyne The base, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 ring Substituted with alkyl or 3 to 8 heterocyclyl substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring contains 1 to 4 selected from O, S, N heteroatoms;
在某些实施方案中，Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24或者取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、吡啶基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环 丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 Or one of the following groups, substituted or unsubstituted: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, Pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclopropylcyclopropyl, cyclopropyl Cyclobutyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl base, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspiro Cyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, Cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl base, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidine Butyl, nitrogen heterocycle Butylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazeterocycle Butyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropyrrolidyl, cyclopentylspiroazetidine Heterocyclylbutyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrrolidyl, azetidinylspiro Azetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidinyl, pyrrolidinylspiropiperidine base, piperidylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano -4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
在某些实施方案中，Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C2-4炔基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的烷基、烷氧基、烷硫基、炔基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3 -12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, Aryl, heteroaryl or heterocyclyl are optionally substituted with 1 to 4 C 1-4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, and halogen. Alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, so The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C2-4炔基、C3-6环烷基、C5-10桥环烷基、C5-12螺环烷基、C4-12并环烷基、C6-10芳基、5-6元杂芳基、4-8元杂环基、5-10元杂桥环、5-12元杂螺环、5-12元杂并环，所述的烷基、烷氧基、烷硫基、炔基、环烷基、芳基、杂芳基、杂环基、杂桥环、杂螺环或杂并环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基、杂环基、杂桥环、杂螺环或杂并环含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3 -6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4- 8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocycle, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group , aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospirocycle or heterocyclic ring optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or Substituted with 3 to 8 heterocyclyl substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24或者取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶 基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代(优选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、CF3、CHF2、甲基、乙基、甲氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基的取代基所取代)，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b3 , R b4 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 - R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, Ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-Diazepanyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl , cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocycle Butyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclobutyl Pentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutyl cyclopentapyrrolidinyl, cyclobutylazetidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl Hexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinyl azo Heterocyclylbutyl, pyrrolidinopyrrolidyl, pyrrolidinopiperidinyl, piperidinaazetidinyl, piperidine cyclobutylspiropyrrolidyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropyrrolidyl, cyclopentylspiroazetidinyl, Cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, azetidinylspiroazetidinyl , azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinyl Spiroazetidinyl, piperidinylspiropiperidinyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl (preferably by 1 to 4 selected from Deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, ethyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azepine Substituted by substituents of cyclobutyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, cyclobutylspirocyclobutyl), the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，选自 In certain embodiments, Selected from
在某些实施方案中，X各自独立的选自NH、O或S；In certain embodiments, each X is independently selected from NH, O, or S;
在某些实施方案中，X各自独立的选自NH、O；In certain embodiments, X is each independently selected from NH, O;
在某些实施方案中，Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-6环烷基或4-10元杂环基，所述的环烷基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, and the cycloalkyl , alkenyl, alkynyl, heterocyclyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen Substituted with substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;
在某些实施方案中，Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-6环烷基或4-8元杂环基，所述的环烷基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, and the cycloalkyl , alkenyl, alkynyl, heterocyclyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen Substituted with substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;
在某些实施方案中，Rb23各自独立的选自乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉，所述的乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；In certain embodiments, each R b23 is independently selected from vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepine base, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the vinyl group, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Heterocyclylbutyl, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine are optionally selected from 1 to 4 F, Cl , Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkyl Substituted by an oxygen substituent;
在某些实施方案中，Rb24各自独立的选自C1-4烷氧基、C3-6环烷基氧基、C3-6环烷基或4-10元杂环基，所述的烷氧基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b24 is independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, The alkoxy group, cycloalkyl group, cycloalkyloxy group and heterocyclic group are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, Substituted with C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb24各自独立的选自C1-4烷氧基、C3-6环烷基氧基、C3-6环烷基或4-8元杂环基，所述的烷氧基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧 基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b24 is independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, The alkoxy group, cycloalkyl group, cycloalkyloxy group and heterocyclic group are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb24各自独立的选自甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉，所述的甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；In certain embodiments, each R b24 is independently selected from methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetamine Butyl, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the methoxy, ethoxy, propoxy base, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxolane base, oxanyl, piperidine or morpholine optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen Substituted with C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents;
在某些实施方案中，m1各自独立的选自0、1、2或3；In certain embodiments, each m1 is independently selected from 0, 1, 2, or 3;
在某些实施方案中，m2各自独立的选自0、1、2或3；In certain embodiments, each m2 is independently selected from 0, 1, 2, or 3;
在某些实施方案中，m2各自独立的选自0、1、2；In certain embodiments, m2 is each independently selected from 0, 1, and 2;
在某些实施方案中，Rb7选自H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、甲基、乙基、乙炔基、丙炔基、炔丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-吗啉基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2O(CH2)2OCH3、-CH2O-环丁基、-CH2O-环丙基、-CH2OCH2-环丁基、-CH2OCH2-环丙基、-CH2NH-环丁基、-CH2NH-环丙基、-CH2OCH2-氧杂环丁基、-CH2OCH2-氧杂环丙基，所述的甲基、乙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氧杂环丁基、氧杂环戊基、哌啶基或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的、C2-4炔基、C3-8环烷基或3至8杂环基取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , methyl, ethyl, ethynyl, propynyl, Propargyl, -CH 2 -cyclopropyl , -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxo Heterocyclopentyl, -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O-cyclobutyl, -CH 2 O - cyclopropyl, -CH 2 OCH 2 -cyclobutyl, -CH 2 OCH 2 -cyclopropyl, -CH 2 NH-cyclobutyl, -CH 2 NH-cyclopropyl, -CH 2 OCH 2 -oxetanyl, -CH 2 OCH 2 -oxetanyl, the methyl, ethyl, ethynyl, propynyl, and propargyl groups , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, oxolyl, piperidyl or morpholine optionally substituted by 1 to 4 Each is selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl , C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents substituted, the heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
在某些实施方案中，Rb7选自取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、环戊基并环戊基、环戊基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b7 is selected from one of the following groups, substituted or unsubstituted: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, morpholine, phenyl, thiophene base, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocycle Butyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclobutyl Pentylspirocyclohexyl, cyclohexylspirocyclohexyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano -4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
在某些实施方案中，Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2或者任选取代的如下基团之一：乙炔基、丙炔基、炔丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-吗啉基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2O(CH2)2OCH3、-CH2O-环丁基、-CH2O-环丙基、-CH2OCH2-环丁基、-CH2OCH2-环丙基、-CH2NH-环丁基、-CH2NH-环丙基、-CH2OCH2-氧杂环丁基、-CH2OCH2-氧杂环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、环戊基并环戊基、环戊基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己 基螺环己基、当被取代时，被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 or optionally substituted one of the following groups: ethynyl, propynyl, propargyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxanyl , -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O-cyclobutyl, -CH 2 O-cyclopropyl, -CH 2 OCH 2 -cyclobutyl, -CH 2 OCH 2 -cyclopropyl, -CH 2 NH-cyclobutyl, -CH 2 NH-cyclo Propyl, -CH 2 OCH 2 -oxetanyl, -CH 2 OCH 2 -oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazine base, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl Spirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexyl base spirocyclohexyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen, cyano Substituted with C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocycle The base contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb6选自C3-8环烷基、-CH2-C3-8环烷基或-CH2CH2-C3-8环烷基，所述的环烷基优选环丙基、环丁基、环戊基、环己基，所述Rb6任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b6 is selected from C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, or -CH 2 CH 2 -C 3-8 cycloalkyl, said cycloalkyl The group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the R b6 is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl Or substituted by 3 to 8 heterocyclyl substituents, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，选自 In certain embodiments, Selected from
在某些实施方案中，选自B1选自C6-14碳环基或5-14元杂环基，所述的B1被1个Rb1a取代、任选被1至3个Rb1取代，B2选自5-10元杂环基，所述B2任选被1至3个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, Selected from B 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the B 1 is substituted by 1 R b1a , optionally substituted by 1 to 3 R b1 , and B 2 is selected from 5-10 A membered heterocyclic group, the B 2 is optionally substituted by 1 to 3 R b2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，选自B1选自C6-14碳环基或5-14元杂环基，所述的B1任选被1至4个Rb1取代，B2选自5-10元杂环基，所述B2被1个Rb2a取代、任选被1至3个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, Selected from B 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the B 1 is optionally substituted by 1 to 4 R b1 , B 2 is selected from the 5-10 membered heterocyclyl, the B 2 is substituted by 1 R b2a , optionally substituted by 1 to 3 R b2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，选自选自或C5-10螺环，所述的被1至3个选自Rb3a取代，所述的螺环任选被1至3个选自卤素或Rb3a取代；In certain embodiments, Selected from Selected from or C 5-10 spirocycle, as described Substituted by 1 to 3 selected from R b3a , the spiro ring is optionally substituted by 1 to 3 selected from halogen or R b3a ;
在某些实施方案中，B1选自苯基，所述的苯基被3至5个Rb1取代；In certain embodiments, B1 is selected from phenyl substituted with 3 to 5 R b1 ;
在某些实施方案中，Rb3a各自独立的选自OH、NH2、CN、N(C1-4烷基)2、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, R b3a is each independently selected from OH, NH 2 , CN, N(C 1-4 alkyl) 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl or C 1-4 alkoxy substituents;
在某些实施方案中，Rb3a各自独立的选自OH、NH2、CN、N(CH3)2、CF3、-CH2CN、甲基、乙基、甲氧基或乙氧基的取代基所取代；In certain embodiments, each R b3a is independently selected from OH, NH 2 , CN, N(CH 3 ) 2 , CF 3 , -CH 2 CN, methyl, ethyl, methoxy or ethoxy. Substituted by substituents;
在某些实施方案中，Rb1a选自-C1-4亚烷基-(C≡C)-H、-C1-4亚烷基-NH2、-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-NHC1-4烷基、N(C1-4烷基)2、C5-6环烷基、C5-9螺环、5至6元杂芳基、-(C≡C)-CH3、环丙基、环丁基、苯基，所述的-(C≡C)-CH3被1至3个选自F、Cl、 Br、I、OH、NH2、CN、COOH、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的环丙基或环丁基被1至4个选自NH2、CN、COOH、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-OH、-C1-4亚烷基-O-C1-4烷基、C3-6环烷基的取代基所取代，所述的环烷基或杂芳基被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的螺环或苯基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b1a is selected from -C 1-4 alkylene-(C≡C)-H, -C 1-4 alkylene-NH 2 , -C 1-4 alkylene-N (C 1-4 alkyl) 2 , -C 1-4 alkylene-NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 5-6 cycloalkyl, C 5-9 spiro Ring, 5 to 6-membered heteroaryl, -(C≡C)-CH 3 , cyclopropyl, cyclobutyl, Phenyl, the -(C≡C)-CH 3 is 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl or C 3-6 cycloalkyl substituents, the cyclopropyl or cyclobutyl group is substituted by 1 to 4 selected from NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl , -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-OC 1-4 alkyl, C 3-6 ring The alkyl substituent is substituted, and the cycloalkyl or heteroaryl is substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl Oxygen, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents, the spiro ring or phenyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl and C 3-6 cycloalkyl substituents, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb1a选自-CH2NH2、-CH2N(CH3)2、-CH2CH2N(CH3)2、N(CH3)2、C(CH3)2NH2、-(C≡C)-CH3、环丙基、环丁基、环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、苯基，所述的-(C≡C)-CH3被1至3个选自F、Cl、Br、I、OH、NH2、CN、COOH、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的环丙基或环丁基被1至4个选自NH2、CN、COOH、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-OH、-C1-4亚烷基-O-C1-4烷基、C3-6环烷基的取代基所取代，所述的环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基或苯基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b1a is selected from -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 2 NH 2 , -(C≡C)-CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazole base, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, Phenyl, the -(C≡C)-CH 3 is 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, and C 3-6 cycloalkyl, so The cyclopropyl or cyclobutyl group is 1 to 4 selected from NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen Substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 cycloalkyl Substituted with alkyl-OH, -C 1-4 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl substituents, the cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl , oxazolyl, imidazolyl, thiazolyl, triazolyl, 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkoxy group , halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents, the cyclopropylspirocyclobutyl, cyclobutylspiro Cyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl or phenyl are optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl Substituted with a substituent, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb1a选自-CH2NH2、-CH2N(CH3)2、-CH2CH2N(CH3)2、N(CH3)2、C(CH3)2NH2、
In certain embodiments, R b1a is selected from -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 2 NH 2 ,
在某些实施方案中，Rb2a选自-COOH、-CONH2、-(CH2)n-NH2、-(CH2)n-N(C1-4烷基)2、-(CH2)n-NHC1-4烷基、N(C1-4烷基)2、-(CH2)n-OH、-(CH2)n-C2-4炔基、-(CH2)nOC1-4烷基、-(CH2)nO(CH2)nOC1-4烷基、-(CH2)n-O(CH2)nOC3-6环烷基、-C1-4亚烷基-4至6元杂环基、苯基、5至6元杂芳基，所述的亚烷基、烷基、环烷基、杂环基、苯基、杂芳基、炔基任选被被1至3个选自F、Cl、Br、I、OH、NH2、CN、COOH、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧 基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基的取代基所取代，所述的杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b2a is selected from -COOH, -CONH 2 , -(CH 2 ) n -NH 2 , -(CH 2 ) n -N(C 1-4 alkyl) 2 , -(CH 2 ) n -NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -(CH 2 ) n -OH, -(CH 2 ) n -C 2-4 alkynyl, -(CH 2 ) n OC 1-4 alkyl, -(CH 2 ) n O(CH 2 ) n OC 1-4 alkyl, -(CH 2 ) n -O(CH 2 ) n OC 3-6 cycloalkyl, -C 1 -4 alkylene - 4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, The alkynyl group is optionally 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1- 4 alkyl, C 1-4 alkoxy Substituted with substituents such as halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, and C 3-6 cycloalkyl, the heteroaryl group contains 1 to 4 selected from O , S, N heteroatoms;
在某些实施方案中，Rb2a选自-COOH、-CONH2、-CH2NH2、C(CH3)2OH、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2OCH3、-CH2OCH2CH2O-环丙基、-CH2N(CH3)2、-CH2CH2N(CH3)2、苯基、 In certain embodiments, R b2a is selected from -COOH, -CONH 2 , -CH 2 NH 2 , C(CH 3 ) 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 2 O-cyclopropyl, -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , phenyl,
任选地，B不为 Optionally, B is not
在某些实施方案中，B选自表B-1所示的结构片段之一：In certain embodiments, B is selected from one of the structural fragments shown in Table B-1:
表B-1















Table B-1















在某些实施方案中，B选自表B-2所示结构之一；In certain embodiments, B is selected from one of the structures shown in Table B-2;
表B-2






Table B-2






在某些实施方案中，q各自独立的选自0、1、2、3、4、5或6；In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;
在某些实施方案中，q各自独立的选自0、1、2、3或4；In certain embodiments, each q is independently selected from 0, 1, 2, 3, or 4;
在某些实施方案中，q各自独立的选自0、1或2；In certain embodiments, each q is independently selected from 0, 1, or 2;
在某些实施方案中，n1、n2、n3各自独立的选自0、1、2或3；In certain embodiments, n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;
在某些实施方案中，p1或p2各自独立的选自0、1、2、3、4或5；In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
在某些实施方案中，p1或p2各自独立的选自0、1、2或3；In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, or 3;
在某些实施方案中，p1或p2各自独立的选自0、1或2；In certain embodiments, p1 or p2 are each independently selected from 0, 1 or 2;
在某些实施方案中，K选自K1、K2、K3、K4；In certain embodiments, K is selected from K1, K2, K3, K4;
在某些实施方案中，K1选自 In certain embodiments, K1 is selected from
在某些实施方案中，K1选自 In certain embodiments, K1 is selected from
在某些实施方案中，K2选自 In certain embodiments, K2 is selected from
在某些实施方案中，K2选自 In certain embodiments, K2 is selected from
在某些实施方案中，K3选自 In certain embodiments, K3 is selected from
在某些实施方案中，K3选自 In certain embodiments, K3 is selected from
在某些实施方案中，K4选自 在某些实施方案中，K4选自 In certain embodiments, K4 is selected from In certain embodiments, K4 is selected from
在某些实施方案中，E各自独立地选自C3-10碳环、C6-10芳环、3-12元杂环或5-12元杂芳环，所述杂环或杂芳环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each E is independently selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 3-12 membered heterocyclic ring, or a 5-12 membered heteroaromatic ring. Contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，E各自独立地选自C3-10碳环、苯环、4-12元杂环、5-12元杂芳环，所述杂环或杂芳环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each E is independently selected from a C 3-10 carbocyclic ring, a benzene ring, a 4-12 membered heterocyclic ring, a 5-12 membered heteroaromatic ring, and the heterocyclic or heteroaromatic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，E各自独立地选自苯环、5-6元杂芳环，所述杂环或杂芳环含有1至3个(例如1、2、3个)选自O、S、N的杂原子；In certain embodiments, E is each independently selected from a benzene ring, a 5-6 membered heteroaromatic ring, and the heterocyclic ring or heteroaromatic ring contains 1 to 3 (e.g., 1, 2, 3) selected from O, Heteroatoms of S and N;
在某些实施方案中，E各自独立地选自苯环、吡啶环、哒嗪环、吡嗪环、嘧啶环、吡咯环、吡唑环、咪唑环、噻唑环、呋喃环、噻吩环、噁唑环、吲哚啉环、异吲哚啉环、1,2,3,4-四氢喹啉环或1,2,3,4-四氢异喹啉环；In certain embodiments, E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring, oxane ring Azole ring, indoline ring, isoindoline ring, 1,2,3,4-tetrahydroquinoline ring or 1,2,3,4-tetrahydroisoquinoline ring;
在某些实施方案中，E各自独立地选自苯环、吡啶环、哒嗪环、吡嗪环、嘧啶环、吡咯环、吡唑环、咪唑环、噻唑环、呋喃环、噻吩环或噁唑环；In certain embodiments, each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxane ring. azole ring;
在某些实施方案中，E各自独立地选自苯环、吡啶环、哒嗪环、吡嗪环、嘧啶环；In certain embodiments, E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring;
在某些实施方案中，E各自独立的选自苯环或吡啶环；In certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;
在某些实施方案中，A选自C3-10碳环、C6-10芳环、3-10元杂环或5-10元杂芳环，所述杂环或杂芳环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, A is selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 3-10 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring containing 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，A选自C3-8碳环、苯环、4-7元杂环或5-6元杂芳环，所述杂环或杂芳环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, A is selected from a C 3-8 carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，A选自苯环、吡啶环、哒嗪环、吡嗪环、嘧啶环、吡咯环、吡唑环、咪唑环、噻唑环、呋喃环、噻吩环或噁唑环；In certain embodiments, A is selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;
在某些实施方案中，A选自苯环或吡啶环；In certain embodiments, A is selected from a benzene ring or a pyridine ring;
在某些实施方案中，F各自独立地选自C3-20碳环、C6-20芳环、3-20元杂环或5-20元杂芳环， 所述杂环或杂芳环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each F is independently selected from a C 3-20 carbocyclic ring, a C 6-20 aromatic ring, a 3-20 membered heterocyclic ring, or a 5-20 membered heteroaromatic ring, The heterocyclic or heteroaromatic ring contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，F各自独立地选自C3-7单环碳环、C4-10并环碳环、C5-12螺环碳环、C5-10桥环碳环、4-7元杂单环、4-10元杂并环、8-15元杂三并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基、5-10元杂芳基、所述杂单环、杂并环、杂螺环、杂桥环或杂芳环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each F is independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 branched carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4 -7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14 aryl group, 5-10 Metaheteroaryl, The heteromonocyclic ring, heteroparacyclic ring, heterospirocyclic ring, heterobridged ring or heteroaromatic ring contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，F各自独立地选自C3-7单环碳环、C4-10并环碳环、C5-12螺环碳环、C5-10桥环碳环、4-7元杂单环、4-10元杂并环、8-15元杂三并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基、5-10元杂芳基、 所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个选自O、S或N的杂原子；In certain embodiments, each F is independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 branched carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4 -7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14 aryl group, 5-10 Metaheteroaryl, The heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
在某些实施方案中，F各自独立地选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、 In certain embodiments, each F is independently selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring,
在某些实施方案中，F各自独立地选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、 In certain embodiments, each F is independently selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring,
在某些实施方案中，F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮基、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、吡啶并吡唑基、哒嗪并 哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、 其左侧与L直接连接；In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopentyl[c]pyridyl , 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, Pyridinidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidine base, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridazinyl, imidazopyrimidinyl, imidazopyridinyl , imidazopyridazinyl, imidazopyridazinyl, pyrazopyridyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridyl, pyrimidopyrazinyl, Pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrazolyl, pyridazino Pyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, Its left side is directly connected to L;
在某些实施方案中，Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或3-12元杂环，所述的杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, Q is each independently selected from bond, -O-, -S-, -CH2- , -NRq- , -CO-, -NRqCO- , -CONRq- , or 3- 12-membered heterocycle, the heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted with CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocycle contains 1 to 4 (for example, 1, 2, 3, 4) selected from O, S, N of heteroatoms;
在某些实施方案中，Q各自独立地选自-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或4-7元杂环，所述的杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, Q is each independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -, or 4-7 Heterocycle, the heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, 4) heterocycles selected from O, S, N atom;
在某些实施方案中，Q各自独立地选自键、C(＝O)、Q1或Q2；In certain embodiments, each Q is independently selected from bond, C(=O), Q1 or Q2;
在某些实施方案中，Q1选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 In certain embodiments, Q1 is selected from bond, CH2 , NH, N( CH3 ), O, S, C(=O), NHC(=O), C(=O)NH, N( CH3 )C(=O), C(=O)N(CH 3 ),
在某些实施方案中，Q2选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；In certain embodiments, Q2 is selected from bond, CH2 , O, S, C(=O), NHC(=O), N( CH3 )C(=O);
在某些实施方案中，Rq选自H或C1-6烷基；In certain embodiments, R q is selected from H or C 1-6 alkyl;
在某些实施方案中，Rq选自H或C1-4烷基；In certain embodiments, R q is selected from H or C 1-4 alkyl;
在某些实施方案中，Rq选自H、甲基、乙基；In certain embodiments, R q is selected from H, methyl, ethyl;
在某些实施方案中，Rk2各自独立地选自键、-CO-、-SO2-、-SO-或-C(Rk3)2-；In certain embodiments, each R k2 is independently selected from bond, -CO-, -SO 2 -, -SO-, or -C(R k3 ) 2 -;
在某些实施方案中，Rk2各自独立地选自-CO-、-SO2-或-C(Rk3)2-；In certain embodiments, each R k2 is independently selected from -CO-, -SO 2 -, or -C(R k3 ) 2 -;
在某些实施方案中，Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基、环烷基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、 C1-4烷氧基、C3-6环烷基的取代基所取代；In certain embodiments, each R k1 is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 Alkoxy group, C 3-6 cycloalkyl group, R k7a , the alkyl group, alkoxy group, and cycloalkyl group are optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, Substituted with substituents of C 1-4 alkoxy and C 3-6 cycloalkyl;
在某些实施方案中，Rk1选自Rk7a；In certain embodiments, Rk1 is selected from Rk7a ;
在某些实施方案中，Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each R k3 is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 (such as 1, 2, 3, 4) substituted by a substituent selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个(例如1、2、3或4个)选自F、Cl、Br、I、OH、NH2的取代基所取代；In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkane group or C 1-4 alkoxy group, the alkyl group or alkoxy group is optionally composed of 1 to 4 (for example, 1, 2, 3 or 4) selected from F, Cl, Br, I, OH, NH 2 Substituted by substituents;
在某些实施方案中，Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基，所述甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基任选被1至4个(例如1、2、3或4个)选自F、Cl、Br、I、OH、NH2的取代基所取代；In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl , isopropyl, methoxy, ethoxy or isopropoxy, the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally replaced by 1 to 4 ( For example, 1, 2, 3 or 4) substituted with substituents selected from F, Cl, Br, I, OH, NH 2 ;
在某些实施方案中，两个Rk3和与二者直接相连的碳原子或环骨架共同形成C3-8碳环或3-8元杂环，两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-8碳环或3-8元杂环，所述碳环或杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, two R k3 and the carbon atom or ring skeleton directly connected to the two together form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring, and two R k1 and the carbon atom or ring skeleton directly connected to the two The carbon atoms or ring skeleton together form a C 3-8 carbocyclic ring or a 3-8 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Substituted with Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，两个Rk3和与二者直接相连的碳原子或环骨架共同形成C3-6碳环或3-7元杂环，两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环或3-7元杂环，所述碳环或杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, two R k3 and the carbon atom or ring skeleton directly connected to the two together form a C 3-6 carbocyclic ring or 3-7 membered heterocyclic ring, and two R k1 and the carbon atom or ring skeleton directly connected to the two The carbon atoms or ring skeleton together form a C 3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 (for example, 1, 2, 3, 4) from F, Substituted with Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so The alkyl group, cycloalkyl group or heterocyclyl group is optionally selected from 1 to 4 (for example, 1, 2, 3, 4) from F, Cl, Br, I, OH, =O, NH 2 , CN, Substituted with COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected from O, Heteroatoms of S and N;
在某些实施方案中，Rk4各自独立的选自H、OH、NH2、CF3、CN、C1-4烷基；In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
在某些实施方案中，Rk5各自独立地选自C(CH3)2、CO、CH2、SO2、 In certain embodiments, each R k5 is independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
在某些实施方案中，Rk5各自独立地选自CO、CH2、SO2或 In certain embodiments, each R k5 is independently selected from CO, CH 2 , SO 2 or
在某些实施方案中，Rk6各自独立地选自CO、CH、SO、SO2、CH2或N；In certain embodiments, each R k6 is independently selected from CO, CH, SO, SO 2 , CH 2 or N;
在某些实施方案中，Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、NRk7a； In certain embodiments, each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
在某些实施方案中，Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、N(CH3)、N(CH2CH3)、N(环丙基)或NH；In certain embodiments, each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
在某些实施方案中，Rk7各自独立地选自CO、CH、N、CH2、O、S、N(CH3)或NH；In certain embodiments, each Rk7 is independently selected from CO, CH, N, CH2 , O, S, N( CH3 ), or NH;
在某些实施方案中，Rk7各自独立地选自CH2、O、N(CH3)或NH；In certain embodiments, each Rk7 is independently selected from CH2 , O, N( CH3 ), or NH;
在某些实施方案中，Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代；In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1 Substituted by -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl substituents;
在某些实施方案中，Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代；In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1 Substituted by -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
在某些实施方案中，Rk7a选自H、C1-4烷基、C3-6环烷基，所述的烷基或环烷基任选被1至4个选自卤素、OH、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, Substituted with substituents of CN, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
在某些实施方案中，Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代；In certain embodiments, Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, the methyl, ethyl, propyl base, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl 1 to 4 are selected from F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl , substituted by substituents of propynyl, propargyl, C 3-6 cycloalkyl;
在某些实施方案中，Rk7a选自H、甲基、乙基、异丙基、环丙基、氧杂环丁基、四氢吡喃基、-CH2CF3、-CH(CH3)CF3、-CH(CH3)-环丙基、-CH2-环丙基、-CH2-乙烯基、-CH2-乙炔基、-CH2CH2-甲氧基；In certain embodiments, R k7a is selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH(CH 3 )-cyclopropyl, -CH 2 -cyclopropyl , -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2 CH 2 -methoxy;
在某些实施方案中，Rk7a选自H、CF3、甲基、乙基、环丙基、-CH2-环丙基；In certain embodiments, R k7a is selected from H, CF 3 , methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;
在某些实施方案中，Rk7a选自H、CH3、CH2CH3、环丙基；In certain embodiments, R k7a is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl;
在某些实施方案中，Rk8各自独立地选自C、N或CH；In certain embodiments, each Rk8 is independently selected from C, N, or CH;
在某些实施方案中，Rk9各自独立地选自键、C(CH3)2、CO、CH2、CH2CH2或SO2；In certain embodiments, each R k9 is independently selected from bond, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
在某些实施方案中，Rk9各自独立地选自CO、SO2或CH2；In certain embodiments, each R k9 is independently selected from CO, SO 2 or CH 2 ;
在某些实施方案中，M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；In certain embodiments, M 1 is selected from the group consisting of bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
在某些实施方案中，M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl, or 4-10 membered heterocyclyl, The alkyl, cycloalkyl or heterocyclyl group is optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, =O, OH, NH 2 , C 1- Substituted with a 4- alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，M3选自-NH-或-O-；In certain embodiments, M 3 is selected from -NH- or -O-;
在某些实施方案中，Rk10选自C1-6烷基，所述的烷基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；In certain embodiments, R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally composed of 1 to 4 (eg, 1, 2, 3, 4) selected from F, Cl, Br, I , substituted by a substituent of =O, OH, C 1-6 alkyl or C 3-6 cycloalkyl;
在某些实施方案中，G选自C6-10芳环或5-10元杂芳环，所述的芳环或者杂芳环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4 烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳环含有1至4个(例如1、2、3、4个)选自N、O、S的杂原子；In certain embodiments, G is selected from a C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring, and the aromatic ring or heteroaromatic ring is optionally substituted by 1 to 4 (for example, 1, 2, 3, 4 ) selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen substituted C 1-4 Substituted with alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heteroaromatic ring contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from N, O, S;
在某些实施方案中，Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio group or -OC(=O)-C 1-6 alkyl group, the alkyl group, alkoxy group or alkylthio group is optionally selected from 1 to 4 (such as 1, 2, 3, 4) Substituted from a substituent of F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 (For example, 1, 2, 3, 4) substituted with substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个(例如1、2、3、4个)选自N、O、S的杂原子；在某些实施方案中，Rk14选自噻唑，所述的噻唑任选被1至4个(例如1、2、3、4个)选自甲基的取代基取代；在某些实施方案中，Rk14选自 In certain embodiments, R k14 is selected from a 5-6 membered heteroaryl group, and the heteroaryl group is optionally composed of 1 to 4 (eg, 1, 2, 3, 4) selected from F, Cl, Br , I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3 -6 cycloalkyl substituents substituted, the heteroaryl group containing 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from N, O, S; in certain embodiments, R k14 is selected from thiazole, and the thiazole is optionally substituted with 1 to 4 (eg, 1, 2, 3, 4) substituents selected from methyl; in certain embodiments, R k14 is selected from
在某些实施方案中，K选自表K-1所示的结构片段之一：In certain embodiments, K is selected from one of the structural fragments shown in Table K-1:
表K-1




Table K-1




在某些实施方案中，K选自表K-2所示的结构片段之一；In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;
表K-2





Table K-2





在某些实施方案中，K选自表K-3所示的结构片段之一：In certain embodiments, K is selected from one of the structural fragments shown in Table K-3:
K-3
K-3
在某些实施方案中，K选自
In certain embodiments, K is selected from
作为本发明的第一种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；q各自独立的选自0、1、2、3、4、5或6；Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, - NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -NR L (CH 2 ) q C(＝O)-, -(CH 2 ) q -C( =O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH＝CH-, -Si( R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)(R L )-, - S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from halogen, OH, CN, Substitution of NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl Substituted with a group; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
每个-Cy-各自独立地选自键或者任选取代的如下基团之一：4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Each -Cy- is independently selected from a bond or one of the optionally substituted groups: 4-8 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterospirocyclic ring Heterobridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl group, Benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, heteroaryl, The heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatoms are selected from S, they are optionally substituted by 1 or 2 =O;
RL2各自独立地选自氘、F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene -OC 1-4 alkyl, -OC 1-4 alkylene -OC 3-10 carbocyclyl, -C 1-4 alkylene- OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene- OC 3-10 carbocyclyl, -OC 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -4 to 10 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, Substituted with hydroxyl-substituted C 1-4 alkyl and C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
B选自 B is selected from
B1选自C5-20碳环基或4-20元杂环基，所述B1任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl. The B 1 is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
B2选自C5-20碳环基或4-20元杂环基，所述B2任选被1至4个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl. The B 2 is optionally substituted by 1 to 4 R b2 . The heterocyclyl contains 1 to 4 selected from O, Heteroatoms of S and N;
V选自 V is selected from
W选自O或S；W is selected from O or S;
Y1、Y2、Y3各自独立地选自键、O、S、NRb5a、C(＝S)、C(＝O)、CONRb5a、NRb5aCO；Y 1 , Y 2 , Y 3 are each independently selected from bonds, O, S, NR b5a , C(=S), C(=O), CONR b5a , NR b5a CO;
P1、P2各自独立地选自 P 1 and P 2 are each independently selected from
v2各自独立地选自0、1、2、3或4； v 2 are each independently selected from 0, 1, 2, 3 or 4;
v1各自独立地选自0、1或2；v 1 are each independently selected from 0, 1 or 2;
Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-ORb22、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-OH、-C1-4亚烷基-O-C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group, C 1-4 alkylthio group, -(CH 2 ) n -R b22 , -OR b22 , -N(R b21 ) 2 , -C(=O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S(＝O) 2 N( R b21 ) 2 , -NR b21 C(=O)R b22 , -NR b21 S(=O) 2 R b22 , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl Or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optional Substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene Substituted by -OH, -C 1-4 alkylene -OC 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy substituents;
Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基或4-8元杂环基，所述的烷基、烷氧基、环烷基、烯基、炔基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C3-6环烷基氧基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-8 yuan Heterocyclyl, the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2. Substituted with substituents of CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, and C 1-4 alkoxy, as described The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
n各自独立的选自0、1、2、3或4；n is independently selected from 0, 1, 2, 3 or 4;
Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4烷基、-C(＝O)N(C1-4烷基)2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-8环烷基、C6-10芳基、5-10元杂芳基、4-10元杂环基、-C1-4亚烷基-4至10元杂环基，所述的亚烷基、CH2、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基氧基、卤素取代的C3-6环烷基、卤素取代的C3-6环烷基氧基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , - C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group , C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C 1-4 alkylene-4 to 10 membered heterocyclyl, so The above-mentioned alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3-6 cycloalkyloxy, 5-6 yuan Substituted with a substituent of a heteroaryl group or a 4-8 membered heterocyclyl group, the heteroaryl group or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, and N;
Rb3、Rb4、Rb6、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 , R b4 , R b6 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio The base, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen Substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with substituents, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
或Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
作为选择，Rb3与Rb5a、Rb1与Rb5a直接连接形成环S，环S选自4至9元含氮杂环基，环S任选被1至4个选自Rs的取代基所取代；Alternatively, R b3 and R b5a , R b1 and R b5a are directly connected to form ring S. Ring S is selected from 4 to 9-membered nitrogen-containing heterocyclic groups. Ring S is optionally substituted by 1 to 4 substituents selected from Rs . replaced;
Rs各自独立的选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、C1-4烷氧基、C3-6 环烷基、5-6元杂芳基或3至8杂环基，所述的烷基、烷氧基、环烷基、杂芳基或者杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 F , Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group or heteroaryl group contains 1 to 4 options Heteroatoms from O, S, N;
Rb5a选自H或Rb5；R b5a is selected from H or R b5 ;
Rb5选自OH、NH2、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3 -6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl Or the heteroaryl group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkyl Substituents of oxygen group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
X各自独立的选自NH、O或S；X is each independently selected from NH, O or S;
m1各自独立的选自0、1、2或3；m1 is each independently selected from 0, 1, 2 or 3;
m2各自独立的选自0、1、2或3；m2 is independently selected from 0, 1, 2 or 3;
Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-6环烷基或4-10元杂环基，所述的环烷基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rb24各自独立的选自C1-4烷氧基、C3-6环烷基氧基、C3-6环烷基或4-10元杂环基，所述的烷氧基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 are each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl. The alkoxy, cycloalkyl The base, cycloalkyloxy group and heterocyclyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S , N heteroatoms;
K选自K1、K2、K3、K4；K is selected from K1, K2, K3, K4;
K1选自 K1 is selected from
K2选自 K2 is selected from
K3选自 K3 is selected from
K4选自 K4 is selected from
Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或3-12元杂环，所述的杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 3-12 membered heterocycles, The heterocyclic ring is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
Rq选自H或C1-6烷基；R q is selected from H or C 1-6 alkyl;
A选自C3-10碳环、C6-10芳环、3-10元杂环或5-10元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；A is selected from C 3-10 carbocyclic ring, C 6-10 aromatic ring, 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring. The heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or heteroatoms of N;
F各自独立地选自C3-20碳环、C6-20芳环、3-20元杂环或5-20元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；Each F is independently selected from C 3-20 carbocyclic ring, C 6-20 aromatic ring, 3-20 membered heterocyclic ring or 5-20 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from Heteroatom of O, S or N;
Rk2各自独立地选自键、-CO-、-SO2-、-SO-或-C(Rk3)2-；R k2 is each independently selected from bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, Rk7a , the alkyl, alkoxy or cycloalkyl is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted by CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, = Substituted with O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S or N heteroatoms;
或者两个Rk3和与二者直接相连的碳原子或环骨架共同形成C3-8碳环或3-8元杂环，两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-8碳环或3-8元杂环，所述碳环或杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atoms or ring skeleton directly connected to them together form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring, and the two R k1 and the carbon atoms or ring skeleton directly connected to them form a C 3-8 carbocyclic ring or 3-8 membered heterocycle. Forming a C 3-8 carbocyclic ring or a 3-8 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl The base or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；M 1 is selected from the group consisting of bonds, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所 取代，所述杂环基含有1至4个选自O、S或N的杂原子；M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkyl, cycloalkyl Or heterocyclyl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
M3选自-NH-或-O-；M 3 is selected from -NH- or -O-;
Rk10选自C1-6烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 ring Substituted by alkyl substituents;
Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents substituted;
Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；R k14 is selected from 5-6 membered heteroaryl groups, and the heteroaryl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkane Substituted by a substituent of a halogen-substituted C 1-4 alkyl group, a hydroxyl-substituted C 1-4 alkyl group, a C 1-4 alkoxy group or a C 3-6 cycloalkyl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
G选自C6-10芳环或5-10元杂芳环，所述的芳环或者杂芳环任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳环含有1至4个选自N、O或S的杂原子；G is selected from C 6-10 aromatic ring or 5-10 membered heteroaromatic ring, and the aromatic ring or heteroaromatic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3. Substituents of CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl Substituted, the heteroaromatic ring contains 1 to 4 heteroatoms selected from N, O or S;
n1、n2、n3各自独立的选自0、1、2或3；n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
p1或p2各自独立的选自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
作为本发明的第二种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B选自 B is selected from
v2各自独立地选自1、2、3或4；v 2 are each independently selected from 1, 2, 3 or 4;
v1各自独立地选自0、1或2；v 1 are each independently selected from 0, 1 or 2;
v3选自0、1、2或3；v 3 is selected from 0, 1, 2 or 3;
v4选自0、1、2或3；v 4 is selected from 0, 1, 2 or 3;
z选自0、1、2或3；z is selected from 0, 1, 2 or 3;
W选自O或S；W is selected from O or S;
的定义与B1相同； The definition of is the same as B 1 ;
B1、B4各自独立的选自C6-14碳环基或5-14元杂环基，所述B1、B4任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl. The B 1 and B 4 are optionally substituted by 1 to 4 R b1 , and the heterocyclic The base contains 1 to 4 heteroatoms selected from O, S, and N;
B2选自C5-10碳环基、5-10元杂环基或B5，所述B2任选被1至4个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 . The B 2 is optionally substituted by 1 to 4 R b2 , and the heterocyclyl contains 1 to 4 optional R b 2 . Heteroatoms from O, S, N;
B3选自C6-14碳环基或4-14元杂环基，所述B3任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl. The B 3 is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
B5选自C12-18三并环、12至18元杂三并环、噻吩基、呋喃基、噻唑基、噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、苯基、苯并C4-6碳环、苯并4至6元杂环、吡唑并C4-6碳环、吡唑并4至6元杂环、三氮唑并C4-6碳环、三氮唑并4至6元杂环、咪唑并C4-6碳环、咪唑并4至6元杂环、噻吩并C4-6碳环、噻吩并4至6元杂环、呋喃并C4-6碳环、呋喃并4至6元杂环、4-7元含氮杂单环烷基、4-10元含氮杂并环烷基、5-12元含氮杂螺环烷基、7-10元含氮杂桥环烷基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基，所述B5任选被1至4个Rb2取代，所述的杂环、杂单环烷基、杂并环烷基、杂螺环烷基、杂桥环烷基含有1至4个选自O、S、N的杂原子；B 5 is selected from C 12-18 tricyclic ring, 12 to 18 membered heterotricyclic ring, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine base, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, triazolo C 4- 6 carbocyclic ring, triazolo 4 to 6 membered heterocyclic ring, imidazo C 4 to 6 carbocyclic ring, imidazo 4 to 6 membered heterocyclic ring, thieno C 4 to 6 carbocyclic ring, thieno 4 to 6 membered heterocyclic ring , furo C 4-6 carbocyclic ring, furo 4- to 6-membered heterocycle, 4-7-membered nitrogen-containing heteromonocycloalkyl, 4-10-membered nitrogen-containing heterocycloalkyl, 5-12-membered nitrogen-containing heterocyclic alkyl Spirocycloalkyl, 7-10-membered nitrogen-containing hetero-bridged cycloalkyl, 3-7-membered monocyclic alkyl, 4-10-membered cycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged ring Alkyl, the B 5 is optionally substituted by 1 to 4 R b2 , the heterocycle, heteromonocycloalkyl, heterocycloalkyl, heterospirocycloalkyl, heterobridged cycloalkyl contains 1 to 4 4 heteroatoms selected from O, S, and N;
Rb5选自OH、NH2、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3 -6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl Or the heteroaryl group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkyl Substituents of oxygen group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4炔基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的炔基、环烷基、芳基、 杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl, cycloalkyl, aryl , The heteroaryl or heterocyclic group is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, and cyano. Substituted with substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl Or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C2-4炔基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的烷基、烷氧基、烷硫基、炔基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group or The heterocyclic group is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and cyano. Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, the heteroaryl or heterocyclic The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
或Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
其余基团定义与本发明第一种实施方案相同。The definitions of the remaining groups are the same as in the first embodiment of the present invention.
作为本发明的第三种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B选自 B is selected from
环S选自5元、6元或7元含有1或2个氮原子的环，环S任选被1至4个Rs取代；Ring S is selected from a 5-membered, 6-membered or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;
Rs各自独立的选自F、Cl、Br、I、OH、NH2、-NHC1-4烷基、-N(C1-4烷基)2、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基或者环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基或C1-4烷氧基的取代基所取代；R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy group, C 3-6 cycloalkyl group, the alkyl group, alkoxy group or cycloalkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , Substituted by CN, C 1-4 alkyl or C 1-4 alkoxy substituents;
B1、B4各自独立的选自苯基、萘基、C6-12碳环基、5-10元杂芳基、5-10元杂环基、C10-14三环碳环基、12至14元三环杂环基，所述B1、B4任选被1至4个Rb1所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;
B2选自C6-10芳基、5-7元杂环基、5-10元杂芳基或5-10元杂并环、5-10元杂桥环，所述B2任选被1至4个Rb2取代，所述的杂芳基、杂环基、杂并环、杂桥环含有1至4个选自O、S、N的杂原子；B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5-10 membered heterobridged ring, and the B 2 is optionally replaced by 1 to 4 R b2 substituted, and the heteroaryl, heterocyclyl, heterocyclic, and heterobridged rings contain 1 to 4 heteroatoms selected from O, S, and N;
B3选自5-12元杂芳基、C6-7碳环基、C6-10并碳环基、C6-12螺碳环基、C7-12桥碳环基、4-7元单环杂环基、7-14元杂并环、7-14元杂螺环，所述B3任选被1至4个Rb1所取代，所述的杂芳基、杂环基、杂并环、杂螺环含有1至4个选自O、S、N的杂原子；B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 1-membered monocyclic heterocyclyl, 7-14-membered heterocyclic, 7-14-membered heterospirocyclic, the B 3 is optionally substituted by 1 to 4 R b1 , the heteroaryl, heterocyclyl, Heterocyclic rings and heterospirocyclic rings contain 1 to 4 heteroatoms selected from O, S, and N;
Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4烷基、-C(＝O)N(C1-4烷基)2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-8环烷基、C6-10芳基、5至6元杂芳基、4至8元杂环基、-C1-4亚烷基-4至8元杂环基，所述的亚烷基、CH2、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、NH2、-NHC1-4烷基、-N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基氧基、卤素取代的C3-6环烷基、卤素取代的C3-6环烷基氧基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , - C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group , C 3-8 cycloalkyl, C 6-10 aryl, 5 to 6-membered heteroaryl, 4 to 8-membered heterocyclyl, -C 1-4 alkylene-4 to 8-membered heterocyclyl, so The above-mentioned alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3 -6 cycloalkyloxy, 5-6-membered heteroaryl or 4-8-membered heterocyclyl substituents, the heteroaryl or heterocyclic group containing 1 to 4 selected from O, S, N heteroatoms;
Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4炔基、C3-6环烷基、C5-10桥环烷基、C5-12螺环烷基、C4-12并环烷基、C6-10芳基、5-6元杂芳基、4-8元杂环基、5-10元杂桥环、5-12元杂螺环、5-12元杂并环，所述的炔基、环烷基、芳基、杂芳基、杂环基、杂桥环、杂螺环或杂并环任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5 -6-membered heteroaryl, 4-8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocyclic, 5-12-membered heterocyclic, the alkynyl, cycloalkyl, aromatic The base, heteroaryl, heterocyclyl, heterobridged ring, heterospiro ring or heterocyclic ring is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkane base, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 hetero Substituted by the substituent of the ring group, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C2-4炔基、C3-6环烷基、C5-10桥环烷基、C5-12螺环烷基、C4-12并环烷基、C6-10芳基、5-6元杂芳基、4-8元杂环基、5-10元杂桥环、5-12元杂螺环、5-12元杂并环，所述的烷基、烷氧基、烷硫基、炔基、环烷基、芳基、杂芳基、杂环基、杂桥环、杂螺环或杂并环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基、杂环基、杂桥环、杂螺环或杂并环含有1至4个选自O、S、N的杂原子； R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5 -10-membered hetero-bridged ring, 5-12-membered heterospiro ring, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group , Heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospirocycle or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
或Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-6环烷基或4-8元杂环基，所述的环烷基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rb24各自独立的选自C1-4烷氧基、C3-6环烷基氧基、C3-6环烷基或4-8元杂环基，所述的烷氧基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the alkoxy, cycloalkyl The base, cycloalkyloxy group and heterocyclyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S , N heteroatoms;
任选地，B选自时，Rb3、Rb4不能同时选自H；Optionally, B is selected from When , R b3 and R b4 cannot be selected from H at the same time;
其余基团定义与本发明第一种或第二种实施方案相同。The definitions of the remaining groups are the same as in the first or second embodiment of the present invention.
作为本发明的第四种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-； L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2- Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3- Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2- Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2- Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4- Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2- Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 )q-NR L C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝ O)-, -C(＝O)-(CH 2 ) q -NR L -, -CH＝CH-, -(C≡C) q -or bond, the -CH 2 -, -CH＝CH - C 1-4 alkyl optionally substituted by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen, Substituted with substituents of hydroxyl-substituted C 1-4 alkyl and cyano-substituted C 1-4 alkyl;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或者任选取代的如下基团之一：4-7元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；q各自独立的选自0、1、2、3或4；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or optionally substituted following groups: 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, Heteroaryl, heteromonocycle, heteroparacycle, heterospirocycle or heterobridged ring contain 1 to 4 heteroatoms selected from O, S, N. When the heteroatoms are selected from S, they are optionally replaced by 1 or 2 =O substitution; q is each independently selected from 0, 1, 2, 3 or 4;
RL各自独立的选自H或C1-6烷基；R L are each independently selected from H or C 1-6 alkyl;
K2选自 K2 is selected from
K3选自 K3 is selected from
A选自C3-8碳环、苯环、4-7元杂环或5-6元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；A is selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring or 5-6 membered heteroaromatic ring. The heterocyclic ring or heteroaromatic ring contains 1 to 4 heterocyclic rings selected from O, S or N. atom;
F各自独立地选自C3-7单环碳环、C4-10并环碳环、C5-12螺环碳环、C5-10桥环碳环、4-7元杂单环、4-10元杂并环、8-15元杂三并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基、5-10元杂芳基、所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个选自O、S或N的杂原子；F is each independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 paracyclic carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 8-15 membered heterotriacyclic ring, 5-12 membered heterospirocyclic ring, 5-10 membered heterobridged ring, C 6-14 aryl group, 5-10 membered heteroaryl group, The heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
表示环选自芳香环或非芳香环； Indicates that the ring is selected from aromatic rings or non-aromatic rings;
E各自独立地选自C3-10碳环、苯环、4-12元杂环、5-12元杂芳环，所述杂环或杂芳环含有1 至4个选自O、S或N的杂原子；Each E is independently selected from C 3-10 carbocyclic ring, benzene ring, 4-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N;
Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或4-7元杂环，所述的杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 4-7 membered heterocycles, wherein The heterocyclic ring is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
Rq选自H或C1-4烷基；R q is selected from H or C 1-4 alkyl;
Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH或NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkyl Oxygen group, the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH 2 ;
或者两个Rk3和与二者直接相连的碳原子或环骨架共同形成C3-6碳环或3-7元杂环，两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环或3-7元杂环，所述碳环或杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atoms or ring skeleton directly connected to them together form a C 3-6 carbocyclic ring or 3-7 membered heterocyclic ring, and the two R k1 and the carbon atoms or ring skeleton directly connected to them together form Forming a C 3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
Rk4各自独立的选自H、OH、NH2、CF3、CN或C1-4烷基；R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;
Rk5各自独立地选自C(CH3)2、CO、CH2、SO2、 R k5 are each independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
Rk6各自独立地选自CO、CH、SO、SO2、CH2或N；R k6 is each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、NRk7a；R k7 are each independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
Rk8各自独立地选自C、N或CH； Rk8 is each independently selected from C, N or CH;
Rk9各自独立地选自键、C(CH3)2、CO、CH2、CH2CH2或SO2；R k9 are each independently selected from keys, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
Rka选自O、S或NH；R ka is selected from O, S or NH;
Rk7a选自H、C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C Substituted with substituents of 2-4 alkenyl, C 2-4 alkynyl, and C 3-6 cycloalkyl;
Rk14选自 R k14 selected from
p1选自0、1、2或3；p1 is selected from 0, 1, 2 or 3;
p2选自0、1、2或3；p2 is selected from 0, 1, 2 or 3;
其余基团定义与本发明第一种、第二种或第三种实施方案相同。The definitions of the remaining groups are the same as in the first, second or third embodiment of the present invention.
作为本发明的第五种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或者任选取代的如下基团之一：4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: 4-7-membered nitrogen-containing heteromonocycle, 4-10-membered nitrogen-containing heterocyclic ring, 5-12-membered Nitrogen-containing heterospirocycle, 7-10 membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group base, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, substituted by 1 to 4 R L2 , the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S , optionally replaced by 1 or 2 =O;
RL各自独立的选自H或C1-4烷基；R L are each independently selected from H or C 1-4 alkyl;
K1选自 K1 is selected from
K4选自 K4 is selected from
Q选自键、C(＝O)；Q is selected from bond, C(=O);
Q1选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 Q1 is selected from bonds, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 ),
Q2选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；Q2 is selected from bonds, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);
E、A各自独立地选自苯环、吡啶环、哒嗪环、吡嗪环、嘧啶环、吡咯环、吡唑环、咪唑环、噻唑环、呋喃环、噻吩环或噁唑环； E and A are each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;
F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮基、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、吡啶并吡唑基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、 其左侧与L直接连接；F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridimidazolyl, benzo Imidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl , benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, Imidazopyridazinyl, pyrazopyridinyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidine Pyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrazolyl, pyridazinopyridazinyl, pyridazinopyridazinyl, pyrazinopyrazinyl, Its left side is directly connected to L;
Rka选自O、S或NH；R ka is selected from O, S or NH;
Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基，所述甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基任选被1至4个选自F、Cl、Br、I、OH、NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy methyl, ethoxy or isopropoxy, the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted by 1 to 4 selected from F, Cl, Br, Substituted by I, OH, NH 2 substituents;
Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代； Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl Substituted with substituents of C 3-6 cycloalkyl group;
p1或p2各自独立的选自0、1或2；p1 or p2 are each independently selected from 0, 1 or 2;
其余基团定义与本发明第二、三、或四种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third, or fourth embodiments of the present invention.
作为本发明的第六种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
RL选自H、甲基或乙基；R L is selected from H, methyl or ethyl;
q各自独立的选自0、1或2； q is independently selected from 0, 1 or 2;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡啶酮、三嗪基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶、吡唑并吡啶基、吡唑并吡嗪基、吡唑并嘧啶基、苯并噻吩基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、苯并吡咯基、三氮唑并吡啶基、三氮唑并嘧啶基、三氮唑并哒嗪基、三氮唑并吡嗪基、三氮唑并噻唑基、三氮唑并噁唑基、三氮唑并吡唑基、三氮唑并吡咯基、三氮唑并咪唑基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrole base, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridyl , pyrazolopyrazinyl, pyrazopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl , triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyridinyl, triazolothiazolyl, triazoloxazolyl, triazolo Pyrazolyl, triazolopyrrolyl, triazoloimidazolyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl Butylcyclobutyl, cyclobutylcyclohexyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl , cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidine cyclobutyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl Heterocyclylbutyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl , pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidyl, piperidyl azetidinyl, piperidyl pyrrolidinyl, piperidyl piperidyl Aldyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentyl Spiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidinyl, Azetidinylspiroazetidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiro Piperidinyl, When substituted, by 1 to 4 R L2 ;
RL2各自独立的选自氘、F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene-OC 1-2 alkyl, -OC 1-2 alkylene-OC 3-6 carbocyclyl , -C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl , the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylene group, carbocyclic group or heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, COOH, CN , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl Substituted with oxygen, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
B1、B4各自独立的选自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、3-异喹啉酮基、喹唑啉基、3,4-二氢-1H-苯并吡喃基、1,2,3,4-四氢喹啉基、苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、 所述的B1、B4任选被1至4个Rb1所取代；B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, 3- Isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-tetrahydroquinolyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, The B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;
B2选自取代或未取代的如下基团之一：苯基、萘基、吡唑基、咪唑基、三氮唑基、噻唑基、噁唑基、异噁唑基、噻吩基、吡啶基、苯并吡咯基、苯并咪唑基、苯并吡唑基、苯并噻唑基、吡唑并四氢吡咯基、3-哒嗪酮基、2-吡啶酮基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、 或B5，当被取代时，被1至4个Rb2取代；B 2 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl , benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4 -Tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, or B5 , when substituted, by 1 to 4 R b2 ;
B5选自 所述B5任选被1至4个Rb2取代；B 5 selected from The B 5 is optionally substituted by 1 to 4 R b2 ;
B3选自取代或未取代的如下基团之一：苯基、萘基、 苯并吡啶基、苯并噻吩基、苯并呋喃基、噻吩基、呋喃基、吡咯基，当被取代时，被1至4个Rb1取代；B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, Benzopyridyl, benzothienyl, benzofuryl, thienyl, furyl, pyrrolyl, when substituted, are substituted by 1 to 4 R b1 ;
Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡 咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、乙炔基、-CH2-CN、-CH2OH、-CH2OMe、-CH2-环丙基、甲氧基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、咪唑基、吡唑基、三氮唑基、四氮唑基的取代基所取代；R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3 , -C(= O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O)(CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy base, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidine base, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, morpholine, pyridyl Rrolidinocyclopentyl, azetidinylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl base spirocyclohexyl, When substituted, 1 to 4 are selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, iso Propyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidine Substituted with substituents such as piperidinyl, morpholinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl;
Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、NH(CH3)、N(CH3)2、CN、NO2、COOH、-C(＝O)NH2或者任选取代的如下基团之一：-CH2OCH2CH3、甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基，当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、甲氧基、乙氧基、吡唑基、吗啉基、氧杂环己基、环丙基、环丁基、环丙基氧基、 的取代基所取代；R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CN, NO 2 , COOH, -C(=O )NH 2 or optionally substituted one of the following groups: -CH 2 OCH 2 CH 3 , methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, Ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl , thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxanyl, cyclopropyl, cyclobutyl, cyclopropyloxy, Substituted by substituents;
Rb3、Rb4各自独立的选自H、OH、NH2或者任选取代的如下基团之一：甲基、乙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基，当被取代时，被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、CF3、CHF2、甲基、甲氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、吡唑基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基的取代基所取代；R b3 and R b4 are each independently selected from H, OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, cyclobutylspirocyclobutyl, when When substituted, it is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl Substituents of base, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, cyclobutylspirocyclobutyl replaced;
或Rb3、Rb4与其相连接的碳原子共同形成任选取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基，当被取代时，被1至4个选自氘、F、Cl、Br、I、OH、NH2、N(CH3)、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazyl Aldyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, are selected from 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , N(CH 3 ), CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C Substituted with 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 optional Heteroatoms from O, S, N;
Rb5选自OH、NH2、甲基、乙基、丙基、异丙基、-(CH2)n-环丙基、-(CH2)n-环丁基、-(CH2)n-环戊基、-(CH2)n-环己基、苯基、吡啶基，所述的-CH2-、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5 is selected from OH, NH 2 , methyl, ethyl, propyl, isopropyl, -(CH 2 ) n -cyclopropyl, -(CH 2 ) n -cyclobutyl, -(CH 2 ) n -Cyclopentyl, -(CH 2 ) n -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, C 1 -4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl Substituted with a substituent, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
n各自独立的选自0、1；n is independently selected from 0 and 1;
Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24或者取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环 丁基、氧杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、吡啶基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or substituted or unsubstituted as follows One of the groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetamine Butyl, oxetanyl, pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclo Propylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutyl Cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropyl Spirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspirocyclohexyl Propylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl , cyclopentaazetidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, Azetidinyl azetidinyl, azetidinyl pyrrolidinyl, azetidinyl piperidinyl, pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidinyl, Pyrrolidopiperidinyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidine base, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropyrolidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl base, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl ,pyrrolidinylspiropyrrolidyl,pyrrolidinylspiropiperidinyl,piperidinylspiroazetidinyl,piperidinylspiropiperidinyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano -4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
Rb7选自H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24或者取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, pyrrolidinyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, cyclopropyl cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, Cyclopent-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocycle Hexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl Azetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentyl Azetidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetamine Butyl azetidinyl, azetidinopyrrolidyl, azetidinopiperidinyl, pyrrolidinaazetidinyl, pyrrolidinopyrrolidyl, pyrrolidinyl Piperidinyl, piperidylazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, ring Butylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropyrolidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiroazetidinyl Hexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropyrolidinyl, pyrrolidinylspiroazetidinyl, pyrrolidine Spiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano -4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
X各自独立的选自NH、O或S；X is each independently selected from NH, O or S;
m2各自独立的选自0、1或2；m2 is each independently selected from 0, 1 or 2;
Rb23各自独立的选自乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉，所述的乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；R b23 is each independently selected from vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl , oxolanyl, oxanyl, piperidine or morpholine, the vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, azepanyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents ;
Rb24各自独立的选自甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丙基氧基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉，所述的甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；R b24 is each independently selected from methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclopropyloxy, cyclobutyl, cyclopentyl, cyclohexyl, azetidine base, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the methoxy, ethoxy, propoxy group , isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl , oxanyl, piperidine or morpholine optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen Substituted with C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents;
K选自表K-1所示的结构片段之一；K is selected from one of the structural fragments shown in Table K-1;
其余基团定义与本发明第二、三、四或五种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third, fourth or fifth embodiments of the present invention.
作为本发明的第七种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
RL2各自独立地选自氘、F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、-OCHF2、-OCF3、甲基、甲氧基、＝O、羟甲基、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代； RL2 is each independently selected from deuterium, F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the optionally substituted following groups: methyl, Ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, - OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, is selected from 1 to 4 F, CHF 2 , CF 3 , -OCHF 2 , -OCF 3 , methyl, methoxy, = Substituted by O, hydroxymethyl, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 substituents;
B选自表B-1或表B-2所示的结构片段之一；B is selected from one of the structural fragments shown in Table B-1 or Table B-2;
K选自表K-2所示的结构片段之一；K is selected from one of the structural fragments shown in Table K-2;
其余基团定义与本发明第二、三、四、五或六种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.
作为本发明的第八种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化 物、前药、代谢产物、药学上可接受的盐或共晶，As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate substances, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,
L选自键或表L-1或表L-2所示的结构片段之一，其中基团左侧与B连接；L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2, in which the left side of the group is connected to B;
其余基团定义与与本发明第二、三、四、五、六或七种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any one of the second, third, fourth, fifth, sixth or seventh embodiments of the present invention.
作为本发明的第九种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the ninth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L的定义与本发明第三、四、五、六或七种实施方案中任意一项相同；The definition of L is the same as any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention;
K的定义与本发明第三、四、五、六或七种实施方案中任意一项相同；The definition of K is the same as any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention;
B的定义与本发明第七种实施方案相同。The definition of B is the same as in the seventh embodiment of the present invention.
作为本发明的第十种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a tenth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自键、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2- Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3- Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3- Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, - Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4- , -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1- Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4- , -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3- Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5- , -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -CH=CH-, -CH＝C(CN)-, -CH＝C(F)-, -C(CN)＝CH-, -C(F)＝CH-, -C≡C-, -C(CH 3 ) 2 - , -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH- , -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;
其余基团定义与本发明第二、三、四、五、六、七、八或九种实施方案中任意一种相同。The remaining group definitions are the same as any one of the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments of the present invention.
作为本发明的第十一种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，As an eleventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,
L选自键、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-；L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-, -Cy1- Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Cy1-, -Ak1- Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-Ak4-;
Ak1、Ak2、Ak3、Ak4各自独立的选自-C(＝O)-、-O-、NH、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-NHCO-； Ak1, Ak2, Ak3, and Ak4 are each independently selected from -C(=O)-, -O-, NH, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)＝CH-, -C(F)＝CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -NHCO-;
Cy1、Cy2、Cy3各自独立的选自取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代；Cy1, Cy2, and Cy3 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, by 1 to 4 R L2 ;
B、K的定义与本发明第二、三、四、五、六、七种实施方案中任意一种相同。The definitions of B and K are the same as any one of the second, third, fourth, fifth, sixth and seventh embodiments of the present invention.
作为本发明的第十二种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，As a twelfth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,
L选自-Cy1-Cy2-；L is selected from -Cy1-Cy2-;
Cy1选自任选取代的如下基团之一：苯基、 所述Cy1任选被1至3个RL2取代；Cy1 is selected from one of the following optionally substituted groups: phenyl, Said Cy1 is optionally replaced by 1 to 3 R L2 ;
Cy2选自所述Cy2任选被1至2个RL2取代；Cy2 is selected from The Cy2 is optionally replaced by 1 to 2 R L2 ;
其余基团定义与本发明第二、三、四、五、六、七种实施方案中任意一种相同。The definitions of the remaining groups are the same as any one of the second, third, fourth, fifth, sixth and seventh embodiments of the present invention.
本发明涉及一种下述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1结构之一。The present invention relates to a following compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.
表E-1










































Table E-1










































表L-1 L基团













Table L-1 L group













表L-2

Table L-2

本发明涉及一种药物组合物，包括本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable carrier.
本发明涉及一种药物组合物，包括治疗有效量的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
在一些实施方案中，本发明的药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。 In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如抑制或降解AR或AR剪切突变体相关疾病如前列腺癌)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的组合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate the disease or condition being treated to some extent (e.g., inhibit or degrade AR or AR cleavage). One or more symptoms of mutant-related diseases such as prostate cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg , 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg , 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250 -300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg , 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.
在一些实施方案中，该药物组合物包括但不限于1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选抑制或降解AR或AR剪切突变体相关疾病(如前列腺癌)。A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable The salt or co-crystal, the therapeutically effective amount is preferably 1-1500 mg, and the disease preferably inhibits or degrades AR or AR splicing mutant-related diseases (such as prostate cancer).
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1000mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose. In some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或 共晶的量与上述药物组合物中其量相同。The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or co-crystals of the compound of the present invention or its stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or The amount of cocrystal is the same as in the pharmaceutical composition described above.
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者上述药物组合物在用于制备治疗与AR或AR剪切突变体活性或表达量相关疾病的药物中的应用。The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the above-mentioned pharmaceutical composition for the preparation of treatment and AR Or application in drugs for diseases related to the activity or expression of AR splicing mutants.
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶、或者上述药物组合物在用于制备治疗与抑制或降解AR或AR剪切突变体相关疾病的药物中的应用。The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatments and Application in drugs that inhibit or degrade AR or AR splice mutant-related diseases.
本发明涉及的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶、或者上述药物组合物的应用，所述的疾病选自前列腺癌。The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions. Selected from prostate cancer.
本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“卤素”是指F、Cl、Br或I。"Halogen" means F, Cl, Br or I.
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halogenated."
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
“烃基”是指取代的或者未取代的、直链或支链的、饱和或不饱和的由碳、氢原子组成的基团。烃基可以是一价、二价、三价或四价。"Hydrocarbyl" refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂 环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, aza Cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidine base, oxazolidinyl, oxazinalkyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。"Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl base, 1-nonenyl, 3-nonenyl, 1-decene, 4-decene, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this definition. Alkenyl groups may be monovalent, divalent, trivalent or tetravalent.
“炔基”是指取代的或者未取代的直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，包括但不限于在主链包括2至10个碳原子、2至6个碳原子、2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"Alkynyl" refers to substituted or unsubstituted linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to in the main chain Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl base, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- Hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or Four prices.
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的C、N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、 苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted C, N, and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, Benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1] Octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O)n(n为0、1或2)的杂原子。非限定性实例包括："Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any may contain 0 to 5 heteroatoms selected from N, O or S(=O)n (n is 0, 1 or 2). Non-limiting examples include:
“螺环”或“螺环基”可以是一价、二价、三价或四价。 "Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： “并环”或“并环基”可以是一价、二价、三价或四价。"Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not Limited to selected from N, S (=O) n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，并环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括 立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected. It may contain 0 or more double bonds and any ring in the ring system. It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”。"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system.
“杂并环”、“杂并环基”、“并环杂环基”或“并杂环基”是指含有杂原子的“并环”。"Heterocycle", "heterocyclyl", "cycloheterocyclyl" or "heterocyclyl" refers to a "paracycle" containing heteroatoms.
“杂螺环”、“杂螺环基”、“螺环杂环基”或“螺杂环基”是指含有杂原子的“螺环”。"Heterospirocycle", "heterospirocyclyl", "spirocycloheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing heteroatoms.
“杂桥环”、“杂桥环基”、“桥环杂环基”或“桥杂环基”是指含有杂原子的“桥环”。"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing heteroatoms.
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含 "Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O)n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include
本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、 -(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基,Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m - C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , -(CH 2 ) m S(=O) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (where m and n are 0 , 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl, alkoxy group, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option, R b and R c can form a five- or six-membered cycloalkyl or heterocyclyl group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged cyclic, spirocyclic or paracyclic groups.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。"Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
“0至X个选自…取代基所取代”是指被0、1、2、3….X个选自…取代基所取代，X选自1至10之间的任意整数。如“0至4个选自…取代基所取代”是指被0、1、2、3或4个选自…取代基所取代。如“0至5个选自…取代基所取代”是指被0、1、2、3、4或5个选自…取代基所取代。如“杂桥环任选被1至4个选自F的取代基所取代”是指杂桥环任选被0、1、2、3或4个选自F的取代基所取代。"Substituted by 0 to X substituents selected from..." means substituted by 0, 1, 2, 3... For example, "substituted with 0 to 4 substituents selected from..." means substituted with 0, 1, 2, 3 or 4 substituents selected from... For example, "substituted with 0 to 5 substituents selected from..." means substituted with 0, 1, 2, 3, 4 or 5 substituents selected from... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from F.
X-Y元的环(X选自小于Y大于等于3的整数，Y选自4至12之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。The ring of ring of elements. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"Tautomers" refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。“IC 50 ” is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).
具体实施方式Detailed ways
以下结合实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。 The technical solution of the present invention will be described in detail below with reference to the examples, but the protection scope of the present invention includes but is not limited thereto.
本文所述反应中使用的化合物是根据本领域技术人员已知的有机合成技术制备的，起始于市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的，供应商包括：泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc. company.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
SEM:THP:Boc：叔丁氧基羰基；Ms：TBS:MTBE:甲基叔丁基醚；Bn:苄基；DIPEA：N,N-二异丙基乙胺；DMAc：N,N-二甲基乙酰胺；DMSO：二甲基亚砜；DCM：二氯甲烷；Cbz:NMP：N-甲基吡咯烷酮；TCFH：四甲基氯代脲六氟磷酸酯；SEM: THP: Boc: tert-butoxycarbonyl; Ms: TBS: MTBE: methyl tert-butyl ether; Bn: benzyl; DIPEA: N,N-diisopropylethylamine; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dimethyl sulfoxide Methyl chloride; Cbz: NMP: N-methylpyrrolidone; TCFH: tetramethylchlorourea hexafluorophosphate;
中间体1的合成：
Synthesis of intermediate 1:
第一步：1B盐酸盐的制备Step 1: Preparation of 1B hydrochloride
将1A(90g,0.50mol)溶解到500mL 2mol/L盐酸乙酸乙酯溶液中，室温反应5h。将反应体系减压浓缩，得粗品1B的盐酸盐(59g)。Dissolve 1A (90g, 0.50mol) into 500mL 2mol/L hydrochloric acid ethyl acetate solution and react at room temperature for 5h. The reaction system was concentrated under reduced pressure to obtain the hydrochloride salt of crude product 1B (59g).
LCMS m/z＝82.3[M+1]+ LCMS m/z＝82.3[M+1] +
第二步：中间体1的制备Step 2: Preparation of Intermediate 1
将上述粗品1B的盐酸盐(59g)溶于500mL DMSO中，加入碳酸氢钠(42g，0.50mol)，室温搅拌10min后，加入100mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(165.6g，0.60mol)，85℃反应5h。将反应液冷却至室温，加入5L水，过滤，收集固体，用500mL水洗涤，将固体鼓风干燥，得粗中间体1(40g)。Dissolve the hydrochloride (59g) of the above crude product 1B in 500mL DMSO, add sodium bicarbonate (42g, 0.50mol), stir at room temperature for 10 minutes, then add 100mL DIPEA and 2-(2,6-dioxopiperidine- 3-yl)-5-fluoroisoindoline-1,3-dione (for synthesis method, see WO2017197056) (165.6g, 0.60mol), react at 85°C for 5h. The reaction solution was cooled to room temperature, 5 L of water was added, filtered, the solid was collected, washed with 500 mL of water, and the solid was air-dried to obtain crude intermediate 1 (40 g).
中间体2的合成：
Synthesis of intermediate 2:
将上述粗品1B的盐酸盐(0.72g)溶于20mL DMSO中，加入2mL DIPEA和2A(合成方法见WO2020239103)(1.80g，6.12mmol)，80℃反应3h。将反应液冷却至室温，加入200mL水，过滤，收集固体，用50mL水洗涤，将固体鼓风干燥，得粗品中间体2(1.3g)。Dissolve the hydrochloride (0.72g) of the above crude product 1B in 20mL DMSO, add 2mL DIPEA and 2A (see WO2020239103 for the synthesis method) (1.80g, 6.12mmol), and react at 80°C for 3 hours. The reaction solution was cooled to room temperature, 200 mL of water was added, filtered, the solid was collected, washed with 50 mL of water, and the solid was air-dried to obtain crude intermediate 2 (1.3 g).
实施例1：制备化合物1
Example 1: Preparation of Compound 1
第一步：1b的制备Step 1: Preparation of 1b
将1a(4.1g,19.80mmol)和4-碘-1H-吡唑(4.22g,21.75mmol)溶于40mL乙腈中，加入碳酸铯(9.68g,29.70mmol)，80℃反应3h。将反应液冷却至室温，加入30mL水和100mL乙酸乙酯，分液，有机相用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩后粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:9)，得到1b(2.40g，收率：38％)。Dissolve 1a (4.1g, 19.80mmol) and 4-iodo-1H-pyrazole (4.22g, 21.75mmol) in 40mL acetonitrile, add cesium carbonate (9.68g, 29.70mmol), and react at 80°C for 3 hours. The reaction solution was cooled to room temperature, 30 mL of water and 100 mL of ethyl acetate were added, and the liquids were separated. The organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate). Ester/petroleum ether (v/v)=1:9), 1b (2.40g, yield: 38%) was obtained.
第二步：1c的制备Step 2: Preparation of 1c
将1b(2.30g,7.18mmol)溶解在20mL四氢呋喃中，加入4mL水，再加入一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min。向反应液中滴加1mol/L稀盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品(2.0g)。将上述粗品(0.5g)溶于10mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.34g，2.54mmol)，室温反应2h后，依次加入三乙胺(0.52g，5.14mmol)和5-三氟甲基吲哚啉(0.38g，2.03mmol)，室温反应18h。向反应液中加入30mL二氯甲烷，加入40mL饱和碳酸氢钠水溶液，分离出有机相，有机相用100mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得1c(0.51g，收率：54％)。Dissolve 1b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min. Add 1 mol/L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL ethyl acetate, separate the liquids, wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Dissolve the above crude product (0.5g) in 10mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.34g, 2.54mmol), react at room temperature for 2h, then add triethylamine (0.52g) , 5.14mmol) and 5-trifluoromethylindoline (0.38g, 2.03mmol), reacted at room temperature for 18h. Add 30 mL of dichloromethane and 40 mL of saturated sodium bicarbonate aqueous solution to the reaction solution to separate the organic phase. The organic phase is washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated on a silica gel chromatography column. Purification (petroleum ether/ethyl acetate (v/v)=5:1) gave 1c (0.51g, yield: 54%).
LCMS m/z＝462.1[M+1]+ LCMS m/z＝462.1[M+1] +
第三步：化合物1的制备Step 3: Preparation of Compound 1
将1c(0.22g，0.48mmol)溶于5mL DMF中，依次加入上述粗品中间体1(0.19g)、TEA(0.15g，1.48mmol)、CuI(18mg，0.095mmol)和PdCl2(PPh3)2(67mg，0.095mmol)，置换氮气三次，80℃反应18h。将反应液冷却至室温，加入50mL水，析出固体，过滤，滤饼用20mL水洗涤，滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得化合物1(0.1g，收率：31％)。Dissolve 1c (0.22g, 0.48mmol) in 5mL DMF, and add the above crude intermediate 1 (0.19g), TEA (0.15g, 1.48mmol), CuI (18mg, 0.095mmol) and PdCl 2 (PPh 3 ) in sequence 2 (67 mg, 0.095 mmol), replaced with nitrogen three times, and reacted at 80°C for 18 hours. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether). /ethyl acetate (v/v)=1:1) to obtain compound 1 (0.1g, yield: 31%).
1H NMR(400MHz,CDCl3)δ8.26(d,1H),8.08(s,1H),7.72–7.56(m,3H),7.51–7.34(m,2H),6.84–6.75(m,1H),6.54(dd,1H),5.20–5.06(m,1H),4.99–4.86(m,1H),4.44–4.26(m,2H),4.13–3.67(m,6H),3.26–3.11(m,2H),2.97–2.63(m,4H),2.53–2.23(m,2H),2.20–2.00(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.26(d,1H),8.08(s,1H),7.72–7.56(m,3H),7.51–7.34(m,2H),6.84–6.75(m,1H ),6.54(dd,1H),5.20–5.06(m,1H),4.99–4.86(m,1H),4.44–4.26(m,2H),4.13–3.67(m,6H),3.26–3.11(m ,2H),2.97–2.63(m,4H),2.53–2.23(m,2H),2.20–2.00(m,2H).
LCMS m/z＝671.1[M+1]+ LCMS m/z＝671.1[M+1] +
实施例2：制备化合物2
Example 2: Preparation of Compound 2
第一步：2b的制备Step 1: Preparation of 2b
将2a(4.1g,19.80mmol)和4-碘-1H-吡唑(4.22g,21.75mmol)溶于40mL乙腈中，加入碳酸铯(9.68g,29.70mmol)，80℃反应3h。将反应液冷却至室温，加入30mL水和100mL乙酸乙酯，分液，有机相用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩后粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:9)，得到2b(2.40g，收率：38％)。Dissolve 2a (4.1g, 19.80mmol) and 4-iodo-1H-pyrazole (4.22g, 21.75mmol) in 40mL acetonitrile, add cesium carbonate (9.68g, 29.70mmol), and react at 80°C for 3 hours. The reaction solution was cooled to room temperature, 30 mL of water and 100 mL of ethyl acetate were added, and the liquids were separated. The organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate). Ester/petroleum ether (v/v)=1:9), 2b (2.40g, yield: 38%) was obtained.
第二步：2c的制备Step 2: Preparation of 2c
将2b(2.30g,7.18mmol)溶解在20mL四氢呋喃中，加入4mL水，再加入一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min，滴加1mol/L稀盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品(2.0g)。将上述粗品(0.51g)溶解在10mL二氯甲烷中，缓慢滴加1-氯-N,N,2-三甲基丙烯胺(0.35g,2.62mmol)，室温反应2h。向反应液中加入三乙胺(0.53g,5.24mmol)和2-氯-4-(三氟甲基)苯胺(0.34g,1.74mmol)，室温反应3h。向反应液中加入20mL饱和碳酸氢钠水溶液，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:3)，得到2c(0.45g,收率：52％)。Dissolve 2b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), react at room temperature for 30min, add 1mol/L dilute hydrochloric acid dropwise to adjust the pH to 6. Add 50 mL of ethyl acetate, separate the layers, wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Dissolve the above crude product (0.51g) in 10 mL of methylene chloride, slowly add 1-chloro-N,N,2-trimethylpropenylamine (0.35g, 2.62mmol) dropwise, and react at room temperature for 2 hours. Triethylamine (0.53g, 5.24mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.34g, 1.74mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 3 hours. Add 20 mL saturated sodium bicarbonate aqueous solution to the reaction solution, extract with 100 mL ethyl acetate, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether) (v/v)=1:3), 2c (0.45g, yield: 52%) was obtained.
第三步：2d的制备Step 3: Preparation of 2d
将2c(0.5g，1.06mmol)溶于5mL DMF中，冰浴冷却至0℃，加入0.08g 60％氢化钠，0℃反应30min后，加入碘甲烷(0.3g，2.11mmol)，0℃反应1h。向反应液中加入50mL水，用50mL乙酸乙酯萃取两次，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝20:1)，得到2d(0.4g，收率：78％)。Dissolve 2c (0.5g, 1.06mmol) in 5mL DMF, cool to 0°C in an ice bath, add 0.08g 60% sodium hydride, react at 0°C for 30 minutes, add methyl iodide (0.3g, 2.11mmol), and react at 0°C 1h. Add 50 mL of water to the reaction solution, extract twice with 50 mL of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20:1 ), obtaining 2d (0.4g, yield: 78%).
LCMS m/z＝484.0[M+1]+ LCMS m/z＝484.0[M+1] +
第四步：化合物2的制备Step 4: Preparation of Compound 2
将2d(0.2g，0.41mmol)、上述粗品中间体1(0.14g)、TEA(0.25g，2.47mmol)、CuI(16mg，0.084mmol)和PdCl2(PPh3)2(29mg，0.041mmol)，置换氮气三次，在氮气保护下加入5mL DMF，60℃反应3h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩后粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1-1:5)，所得粗品再进行手性拆分(仪器及制备柱：采用Waters 150 SFC制备液相，制备柱型号是Chiralpak Column)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：超临界二氧化碳/甲醇和乙腈的混合溶剂。梯度洗脱方法：甲醇和乙腈的混合溶剂由65％等梯度洗脱)，冻干得到化合物2)的手性异构体1(13.1mg，收率：5％)和手性异构体2(11.1mg，收率：4％)。 2d (0.2g, 0.41mmol), the above crude intermediate 1 (0.14g), TEA (0.25g, 2.47mmol), CuI (16mg, 0.084mmol) and PdCl 2 (PPh 3 ) 2 (29mg, 0.041mmol) , replace nitrogen three times, add 5mL DMF under nitrogen protection, and react at 60°C for 3 hours. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/petroleum ether/ Ethyl acetate (v/v) = 100:1-1:5), and the crude product obtained was subjected to chiral separation (instrument and preparative column: Waters 150 SFC was used to prepare the liquid phase, and the preparative column model was Chiralpak Column). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: supercritical carbon dioxide/mixed solvent of methanol and acetonitrile. Gradient elution method: mixed solvent of methanol and acetonitrile (isogradient elution of 65%), freeze-drying to obtain chiral isomer 1 (13.1 mg, yield: 5%) and chiral isomer 2 of compound 2) (11.1 mg, yield: 4%).
化合物2的手性分析方法Chiral analysis method of compound 2
仪器：SHIMADZU LC-30AD sf，色谱柱：Chiralcel AD-3,规格：50mm×4.6mm,3μmInstrument: SHIMADZU LC-30AD sf, column: Chiralcel AD-3, specifications: 50mm×4.6mm, 3μm
流动相A：超临界CO2，流动相B：含0.05％二乙胺的甲醇和乙腈混合溶液，柱温：35℃Mobile phase A: supercritical CO 2 , mobile phase B: mixed solution of methanol and acetonitrile containing 0.05% diethylamine, column temperature: 35°C
流速：3mL/min，波长：220nm，洗脱程序：流动相A:B＝50:50。Flow rate: 3mL/min, wavelength: 220nm, elution program: mobile phase A:B=50:50.
化合物2的手性异构体1的保留时间：0.871minRetention time of chiral isomer 1 of compound 2: 0.871min
化合物2的手性异构体2的保留时间：1.863minRetention time of chiral isomer 2 of compound 2: 1.863min
化合物2的手性异构体1的核磁谱图NMR spectrum of chiral isomer 1 of compound 2
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.83–6.50(m,8H),5.00–4.85(m,1H),4.42–4.31(m,2H),4.14–3.99(m,2H),3.90–3.73(m,1H),3.30–2.64(m,9H),2.39–1.80(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.95(s,1H),7.83–6.50(m,8H),5.00–4.85(m,1H),4.42–4.31(m,2H),4.14–3.99(m ,2H),3.90–3.73(m,1H),3.30–2.64(m,9H),2.39–1.80(m,4H).
LCMS m/z＝693.1[M+1]+ LCMS m/z＝693.1[M+1] +
化合物2的手性异构体2的核磁谱图NMR spectrum of chiral isomer 2 of compound 2
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.83–6.50(m,8H),4.99–4.85(m,1H),4.42–4.30(m,2H),4.13–3.99(m,2H),3.90–3.73(m,1H),3.30–2.64(m,9H),2.37–1.80(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.02(s,1H),7.83–6.50(m,8H),4.99–4.85(m,1H),4.42–4.30(m,2H),4.13–3.99(m ,2H),3.90–3.73(m,1H),3.30–2.64(m,9H),2.37–1.80(m,4H).
LCMS m/z＝693.2[M+1]+ LCMS m/z＝693.2[M+1] +
实施例3：制备化合物3
Example 3: Preparation of Compound 3
化合物3以化合物2c为原料，参考实施例2方法的合成方法得到化合物3的手性异构体1和手性异构体2。Compound 3 uses compound 2c as raw material, and the chiral isomer 1 and chiral isomer 2 of compound 3 are obtained by referring to the synthesis method of Example 2.
化合物3的手性分析方法Chiral analysis method of compound 3
仪器：SHIMADZU LC-30AD sf，色谱柱：Chiralcel AD-3,规格：50mm×4.6mm,3μmInstrument: SHIMADZU LC-30AD sf, column: Chiralcel AD-3, specifications: 50mm×4.6mm, 3μm
流动相A：超临界CO2，流动相B：含0.05％二乙胺的甲醇和乙腈混合溶液，柱温：35℃Mobile phase A: supercritical CO 2 , mobile phase B: mixed solution of methanol and acetonitrile containing 0.05% diethylamine, column temperature: 35°C
流速：3mL/min，波长：220nm，洗脱程序：流动相A:B＝50:50。Flow rate: 3mL/min, wavelength: 220nm, elution program: mobile phase A:B=50:50.
化合物3的手性异构体1的保留时间：0.839minRetention time of chiral isomer 1 of compound 3: 0.839min
化合物3的手性异构体2的保留时间：2.053minRetention time of chiral isomer 2 of compound 3: 2.053min
化合物3的手性异构体1的核磁谱图NMR spectrum of chiral isomer 1 of compound 3
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.81–6.43(m,8H),5.00–4.88(m,1H),4.42–3.29(m,6H),3.20–2.63(m,7H),2.40–0.90(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ7.92(s,1H),7.81–6.43(m,8H),5.00–4.88(m,1H),4.42–3.29(m,6H),3.20–2.63(m ,7H),2.40–0.90(m,7H).
LCMS m/z＝707.2[M+1]+ LCMS m/z＝707.2[M+1] +
化合物3的手性异构体2的核磁谱图NMR spectrum of chiral isomer 2 of compound 3
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.81–6.43(m,8H),5.00–4.88(m,1H),4.44–3.29(m,6H),3.20–2.63(m,7H),2.40–0.90(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ7.93(s,1H),7.81–6.43(m,8H),5.00–4.88(m,1H),4.44–3.29(m,6H),3.20–2.63(m ,7H),2.40–0.90(m,7H).
LCMS m/z＝707.2[M+1]+ LCMS m/z＝707.2[M+1] +
实施例4：制备化合物4
Example 4: Preparation of Compound 4
第一步：4b的制备Step 1: Preparation of 4b
将4a(2g，9.66mmol)和4-碘吡唑(1.8g，9.28mmol)溶于30mL乙腈中，加入碳酸铯(9.44g，28.97mmol)，80℃反应4h。将反应液冷却至室温，用40mL饱和氯化钠溶液洗涤，水相用50mL乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得4b(2.8g，收率：94％)。Dissolve 4a (2g, 9.66mmol) and 4-iodopyrazole (1.8g, 9.28mmol) in 30 mL acetonitrile, add cesium carbonate (9.44g, 28.97mmol), and react at 80°C for 4 hours. The reaction solution was cooled to room temperature, washed with 40 mL of saturated sodium chloride solution, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ Ethyl acetate (v/v)=5:1), to obtain 4b (2.8g, yield: 94%).
LCMS m/z＝321.1[M+1]+ LCMS m/z＝321.1[M+1] +
第二步：4c的制备Step 2: Preparation of 4c
将4b(1.4g，4.37mmol)溶于5mL乙醇中，加入一水合氢氧化锂(0.70g，16.68mmol)和3mL水，40℃反应2h。将反应液冷却至室温，用1mol/L稀盐酸调pH至3，用30mL乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，将浓缩物溶于10mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.88g，6.60mmol)，室温反应2h后，依次加入三乙胺(1.33g，13.14mmol)和3-氯-4-氨基三氟甲苯(1.11g，5.68mmol)，室温反应18h。向反应液中加入50mL二氯甲烷，加入40mL饱和碳酸氢钠水溶液，分离出有机相，有机相用100mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得4c(0.62g，收率：23％)。Dissolve 4b (1.4g, 4.37mmol) in 5mL ethanol, add lithium hydroxide monohydrate (0.70g, 16.68mmol) and 3mL water, and react at 40°C for 2h. Cool the reaction solution to room temperature, adjust the pH to 3 with 1mol/L dilute hydrochloric acid, extract with 30mL ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, dissolve the concentrate in 10mL DCM, add 1 -Chloro-N,N,2-trimethylpropenylamine (0.88g, 6.60mmol), after reacting at room temperature for 2 hours, add triethylamine (1.33g, 13.14mmol) and 3-chloro-4-aminotrifluorotoluene in sequence (1.11g, 5.68mmol), reacted at room temperature for 18h. Add 50 mL of methylene chloride to the reaction solution, add 40 mL of saturated aqueous sodium bicarbonate solution, and separate the organic phase. The organic phase is washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated on a silica gel chromatography column. Purification (petroleum ether/ethyl acetate (v/v)=5:1) gave 4c (0.62g, yield: 23%).
LCMS m/z＝470.0[M+1]+ LCMS m/z＝470.0[M+1] +
第三步：化合物4的制备Step 3: Preparation of Compound 4
将4c(0.30g，0.64mmol)溶于5mL DMF中，依次加入上述粗品中间体1(0.26g)、TEA(0.19g，1.88mmol)、CuI(24mg，0.13mmol)和PdCl2(PPh3)2(90mg，0.13mmol)，置换氮气三次，80℃反应18h。将反应液冷却至室温，加入50mL水，析出固体，过滤，收集滤饼，滤饼用20mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得化合物4(0.12g，收率：28％)。Dissolve 4c (0.30g, 0.64mmol) in 5mL DMF, and add the above crude intermediate 1 (0.26g), TEA (0.19g, 1.88mmol), CuI (24mg, 0.13mmol) and PdCl 2 (PPh 3 ) in sequence 2 (90 mg, 0.13 mmol), replaced with nitrogen three times, and reacted at 80°C for 18 hours. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, collect the filter cake, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product with a silica gel chromatography column After separation and purification (petroleum ether/ethyl acetate (v/v)=1:1), compound 4 (0.12g, yield: 28%) was obtained.
1H NMR(400MHz,CDCl3)δ9.49(s,1H),8.55(d,1H),8.11(s,1H),7.82–7.59(m,4H),7.55–7.48(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.17(d,1H),4.12–4.03(m,2H),3.88–3.74(m,1H),2.96–2.64(m,3H),2.20–2.07(m,1H),1.83–1.67(m,1H),1.00–0.88(m,1H),0.81–0.65(m,2H),0.55–0.40(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ9.49(s,1H),8.55(d,1H),8.11(s,1H),7.82–7.59(m,4H),7.55–7.48(m,1H), 6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.17(d,1H),4.12–4.03(m,2H), 3.88–3.74(m,1H),2.96–2.64(m,3H),2.20–2.07(m,1H),1.83–1.67(m,1H),1.00–0.88(m,1H),0.81–0.65(m ,2H),0.55–0.40(m,1H).
LCMS m/z＝679.1[M+1]+ LCMS m/z＝679.1[M+1] +
实施例5：制备化合物5
Example 5: Preparation of Compound 5
第一步：5a的制备Step 1: Preparation of 5a
将4b(1.25g，3.90mmol)溶于20mL四氢呋喃，将反应体系冷却至-78℃，缓慢滴加LDA溶液(2.0mol/L四氢呋喃/正庚烷(v/v)＝12/25的溶液)(2.34mL，4.68mmol)，继续在-78℃下搅拌30min后，加入碘甲烷(0.92g，6.48mmol)，升至室温反应3h。向反应液中加入40mL饱和氯化钠水溶液，用50mL乙酸乙酯萃取，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得5a(0.88g，收率：67％)。Dissolve 4b (1.25g, 3.90mmol) in 20mL tetrahydrofuran, cool the reaction system to -78°C, and slowly add LDA solution (2.0mol/L tetrahydrofuran/n-heptane (v/v) = 12/25 solution) dropwise (2.34 mL, 4.68 mmol), continued stirring at -78°C for 30 min, then added methyl iodide (0.92 g, 6.48 mmol), and raised to room temperature for reaction for 3 h. Add 40 mL of saturated aqueous sodium chloride solution to the reaction solution, extract with 50 mL of ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate). (v/v)=5:1), 5a (0.88g, yield: 67%) was obtained.
第二步：5b的制备Step 2: Preparation of 5b
将5a(0.87g，2.60mmol)溶于8mL乙醇中，加入一水合氢氧化锂(0.42g，10.00mmol)和4mL水，40℃反应2h。将反应液冷却至室温，用1mol/L稀盐酸调pH至3，用40mL乙酸乙酯萃取，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，将浓缩物溶于8mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.53g，3.97mmol)，室温反应2h后，依次加入三乙胺(0.80g，7.91mmol)和3-氯-4-氨基三氟甲苯(0.67g，3.43mmol)，室温反应19h。向反应液中加入40mL二氯甲烷，加入40mL饱和碳酸氢钠水溶液，分离出有机相，有机相用80mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得5b(0.32g，收率：19％)。Dissolve 5a (0.87g, 2.60mmol) in 8mL ethanol, add lithium hydroxide monohydrate (0.42g, 10.00mmol) and 4mL water, and react at 40°C for 2h. Cool the reaction solution to room temperature, adjust the pH to 3 with 1 mol/L dilute hydrochloric acid, extract with 40 mL ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and dissolve the concentrate in 8 mL DCM , add 1-chloro-N,N,2-trimethylpropenylamine (0.53g, 3.97mmol), react at room temperature for 2 hours, then add triethylamine (0.80g, 7.91mmol) and 3-chloro-4-amino Trifluorotoluene (0.67g, 3.43mmol), reacted at room temperature for 19h. Add 40 mL of methylene chloride to the reaction solution, add 40 mL of saturated aqueous sodium bicarbonate solution, and separate the organic phase. The organic phase is washed with 80 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated on a silica gel chromatography column. Purification (petroleum ether/ethyl acetate (v/v)=5:1) gave 5b (0.32g, yield: 19%).
LCMS m/z＝484.0[M+1]+ LCMS m/z＝484.0[M+1] +
第三步：化合物5的制备Step 3: Preparation of Compound 5
将5b(0.32g，0.66mmol)溶于9mL DMF中，依次加入上述粗品中间体1(0.27g)、TEA(0.20g，1.98mmol)、CuI(24mg，0.13mmol)和PdCl2(PPh3)2(90mg，0.13mmol)，置换氮气三次，80℃反应18h。将反应液冷却至室温，加入50mL水，析出固体，过滤，收集滤饼，滤饼用20mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得化合物5(0.21g，收率：46％)。Dissolve 5b (0.32g, 0.66mmol) in 9mL DMF, and add the above crude intermediate 1 (0.27g), TEA (0.20g, 1.98mmol), CuI (24mg, 0.13mmol) and PdCl 2 (PPh 3 ) in sequence 2 (90 mg, 0.13 mmol), replaced with nitrogen three times, and reacted at 80°C for 18 hours. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, collect the filter cake, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product with a silica gel chromatography column After separation and purification (petroleum ether/ethyl acetate (v/v)=1:1), compound 5 (0.21g, yield: 46%) was obtained.
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.53(d,1H),8.03–7.90(m,2H),7.77(s,1H),7.67(d,1H),7.63–7.58(m,1H),7.54–7.47(m,1H),6.85–6.78(m,1H),6.56(dd,1H),4.99–4.89(m,1H),4.43–4.30(m,2H),4.15–4.03(m,2H),3.90–3.75(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.80–1.68(m,4H),0.86–0.79(m,2H),0.74–0.58(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.24(s,1H),8.53(d,1H),8.03–7.90(m,2H),7.77(s,1H),7.67(d,1H),7.63– 7.58(m,1H),7.54–7.47(m,1H),6.85–6.78(m,1H),6.56(dd,1H),4.99–4.89(m,1H),4.43–4.30(m,2H), 4.15–4.03(m,2H),3.90–3.75(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.80–1.68(m,4H),0.86–0.79(m ,2H),0.74–0.58(m,2H).
LCMS m/z＝693.2[M+1]+ LCMS m/z＝693.2[M+1] +
实施例6：制备化合物6
Example 6: Preparation of Compound 6
第一步：6b的制备Step 1: Preparation of 6b
将6a(4.06g，20.00mmol)与4-碘吡唑(4.27g，22.00mmol)溶于50mL乙腈中，加入碳酸铯(9.77g，30.00mmol)，80℃反应3h。将反应体系冷却至室温，过滤，将滤液减压浓缩，向残留物中加入80mL THF与20mL水溶解，加入一水合氢氧化锂(0.98g，23.36mmol)，室温反应0.5h。将反应体系用浓盐酸调pH至4，减压浓缩，将残留物冻干，将冻干的残留物用80mL  DCM/MeOH(v/v)＝10:1溶解，过滤，将滤液减压浓缩，得粗品(2.7g)。将上述粗品(0.80g)溶于10mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.51g，3.82mmol)，室温反应2h。向反应液中加入2-氯-4-三氟甲基苯胺(0.5g，2.56mmol)和三乙胺(0.77g，7.61mmol)，室温反应16h。向反应液中加入80mL乙酸乙酯，加入30mL饱和碳酸氢钠水溶液，分离出有机相，有机相用30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得6b(0.22g，收率：18％)。Dissolve 6a (4.06g, 20.00mmol) and 4-iodopyrazole (4.27g, 22.00mmol) in 50 mL acetonitrile, add cesium carbonate (9.77g, 30.00mmol), and react at 80°C for 3 hours. Cool the reaction system to room temperature, filter, and concentrate the filtrate under reduced pressure. Add 80 mL THF and 20 mL water to the residue to dissolve, add lithium hydroxide monohydrate (0.98 g, 23.36 mmol), and react at room temperature for 0.5 h. Adjust the pH of the reaction system to 4 with concentrated hydrochloric acid, concentrate under reduced pressure, freeze-dry the residue, and use 80 mL of the lyophilized residue to Dissolve in DCM/MeOH (v/v) = 10:1, filter, and concentrate the filtrate under reduced pressure to obtain crude product (2.7g). Dissolve the above crude product (0.80g) in 10mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.51g, 3.82mmol), and react at room temperature for 2h. 2-Chloro-4-trifluoromethylaniline (0.5g, 2.56mmol) and triethylamine (0.77g, 7.61mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. Add 80 mL of ethyl acetate to the reaction solution, add 30 mL of saturated aqueous sodium bicarbonate solution, and separate the organic phase. The organic phase is washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated on a silica gel chromatography column. After purification (petroleum ether/ethyl acetate (v/v)=5:1), 6b (0.22g, yield: 18%) was obtained.
第二步：化合物6的制备Step 2: Preparation of compound 6
将6b(0.20g，0.43mmol)溶于5mL DMF中，依次加入上述粗品中间体1(0.16g)、TEA(0.13g，1.28mmol)、CuI(0.008g，0.042mmol)和PdCl2(PPh3)2(0.030g，0.043mmol)，置换氮气三次，55℃反应1h。将反应液冷却至室温，加入50mL水，析出固体，过滤，滤饼用10mL水洗涤，收集滤饼，将滤饼用30mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得化合物6(0.10g，收率：35％)。Dissolve 6b (0.20g, 0.43mmol) in 5mL DMF, and add the above crude intermediate 1 (0.16g), TEA (0.13g, 1.28mmol), CuI (0.008g, 0.042mmol) and PdCl 2 (PPh 3 ) 2 (0.030g, 0.043mmol), replaced with nitrogen three times, and reacted at 55°C for 1 hour. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, wash the filter cake with 10 mL of water, collect the filter cake, dissolve the filter cake with 30 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product with a silica gel chromatography column After separation and purification (petroleum ether/ethyl acetate (v/v) = 1:1), compound 6 (0.10 g, yield: 35%) was obtained.
1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.54(d,1H),8.04(s,1H),8.00(s,1H),7.82–7.55(m,4H),6.86–6.78(m,1H),6.56(dd,1H),5.00–4.88(m,1H),4.45–4.30(m,2H),4.15–4.02(m,2H),3.90–3.75(m,1H),3.00–2.62(m,3H),2.21–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ9.42(s,1H),8.54(d,1H),8.04(s,1H),8.00(s,1H),7.82–7.55(m,4H),6.86– 6.78(m,1H),6.56(dd,1H),5.00–4.88(m,1H),4.45–4.30(m,2H),4.15–4.02(m,2H),3.90–3.75(m,1H), 3.00–2.62(m,3H),2.21–2.08(m,1H).
LCMS m/z＝673.0[M-1]- LCMS m/z＝673.0[M-1] -
实施例7：制备化合物7
Example 7: Preparation of Compound 7
第一步：7b的制备Step 1: Preparation of 7b
将2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸(0.5g，1.78mmol)(合成方法见WO2019074962)溶于10mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.36g，2.69mmol)，室温反应2h后，依次加入三乙胺(1.09g，10.77mmol)和7a(0.34g，1.82mmol)，室温反应12h。向反应液中加入50mL二氯甲烷，加入50mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-3:1)，得7b(0.5g，收率：63％)。Dissolve 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid (0.5g, 1.78mmol) (see WO2019074962 for synthesis method) in 10mL DCM, add 1-chloro-N , N,2-trimethylpropenylamine (0.36g, 2.69mmol), reacted at room temperature for 2h, then added triethylamine (1.09g, 10.77mmol) and 7a (0.34g, 1.82mmol) in sequence, and reacted at room temperature for 12h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1 :0-3:1) to obtain 7b (0.5g, yield: 63%).
第二步：化合物7的制备Step 2: Preparation of Compound 7
将7b(0.42g，0.93mmol)、上述粗品中间体1(0.32g)、TEA(0.57g，5.63mmol)、CuI(36mg，0.18mmol)和PdCl2(PPh3)2(66mg，0.094mmol)加入5mL DMF中，氮气氛围55℃反应1.5h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2)，得化合物7(0.1g，收率：16％)。7b (0.42g, 0.93mmol), the above crude intermediate 1 (0.32g), TEA (0.57g, 5.63mmol), CuI (36mg, 0.18mmol) and PdCl 2 (PPh 3 ) 2 (66mg, 0.094mmol) Add 5 mL of DMF and react at 55°C for 1.5 h in a nitrogen atmosphere. The reaction solution was cooled to room temperature, 50 mL of water was added, suction filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ Dichloromethane/ethyl acetate (v/v)=1:1:2), compound 7 (0.1g, yield: 16%) was obtained.
1H NMR(400MHz,CDCl3)δ8.36(d,1H),7.95(s,1H),7.72–7.60(m,3H),7.52–7.44(m,1H),7.42–7.34(m,1H),6.85–6.75(m,1H),6.55(dd,1H),5.00–4.87(m,1H),4.44–4.30(m,2H),4.15–4.00(m,2H),3.89–3.73(m,1H),3.25–3.12(m,2H),3.06–2.62(m,5H),2.20–2.04(m,1H),1.89(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.36(d,1H),7.95(s,1H),7.72–7.60(m,3H),7.52–7.44(m,1H),7.42–7.34(m,1H ),6.85–6.75(m,1H),6.55(dd,1H),5.00–4.87(m,1H),4.44–4.30(m,2H),4.15–4.00(m,2H),3.89–3.73(m ,1H),3.25–3.12(m,2H),3.06–2.62(m,5H),2.20–2.04(m,1H),1.89(s,6H).
LCMS m/z＝659.2[M+1]+ LCMS m/z＝659.2[M+1] +
实施例8：制备化合物8
Example 8: Preparation of Compound 8
化合物8以化合物8a为原料，参考实施例1得到。Compound 8 was obtained by referring to Example 1 using compound 8a as a raw material.
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.73–7.17(m,6H),6.82–6.75(m,1H),6.53(dd,1H),4.99–4.85(m,3H),4.40–4.28(m,2H),4.27–4.16(m,2H),4.10–4.00(m,2H),3.86–3.72(m,1H),3.08–2.63(m,7H),2.19–1.88(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.99(s,1H),7.73–7.17(m,6H),6.82–6.75(m,1H),6.53(dd,1H),4.99–4.85(m,3H ),4.40–4.28(m,2H),4.27–4.16(m,2H),4.10–4.00(m,2H),3.86–3.72(m,1H),3.08–2.63(m,7H),2.19–1.88 (m,3H).
LCMS m/z＝671.8[M+1]+ LCMS m/z＝671.8[M+1] +
实施例9：制备化合物9
Example 9: Preparation of Compound 9
化合物9以化合物9a为原料，参考实施例7得到。Compound 9 was obtained by referring to Example 7 using compound 9a as a raw material.
1H NMR(400MHz,CDCl3)δ8.35(d,1H),8.08–7.99(m,1H),7.74–7.60(m,3H),7.56–7.48(m,1H),7.39(s,1H),6.84–6.76(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.86–3.74(m,1H),3.24–3.12(m,2H),3.04–2.65(m,5H),2.19–2.08(m,1H),1.89(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.35(d,1H),8.08–7.99(m,1H),7.74–7.60(m,3H),7.56–7.48(m,1H),7.39(s,1H ),6.84–6.76(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.86–3.74(m ,1H),3.24–3.12(m,2H),3.04–2.65(m,5H),2.19–2.08(m,1H),1.89(s,6H).
LCMS m/z＝616.2[M+1]+ LCMS m/z＝616.2[M+1] +
实施例10：制备化合物10
Example 10: Preparation of Compound 10
化合物10以化合物10a为原料，参考实施例1得到。Compound 10 was obtained by referring to Example 1 using compound 10a as a raw material.
1H NMR(400MHz,CDCl3)δ8.40–8.25(m,1H),7.98(s,1H),7.71–7.60(m,3H),7.58–7.49(m,1H),7.40(s,1H),6.83–6.76(m,1H),6.54(dd,1H),4.98–4.88(m,1H),4.40–4.26(m,2H),4.10–3.98(m,2H),3.85–3.72(m,1H),3.57–3.43(m,2H),3.12–2.65(m,9H),2.19–1.90(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.40–8.25(m,1H),7.98(s,1H),7.71–7.60(m,3H),7.58–7.49(m,1H),7.40(s,1H) ),6.83–6.76(m,1H),6.54(dd,1H),4.98–4.88(m,1H),4.40–4.26(m,2H),4.10–3.98(m,2H),3.85–3.72(m ,1H),3.57–3.43(m,2H),3.12–2.65(m,9H),2.19–1.90(m,3H).
LCMS m/z＝628.7[M+1]+ LCMS m/z＝628.7[M+1] +
实施例11：制备化合物11
Example 11: Preparation of Compound 11
以化合物11a和2b为原料，参照实施例1的合成方法得到化合物11(0.38g)Using compounds 11a and 2b as raw materials, compound 11 (0.38g) was obtained by referring to the synthesis method of Example 1.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.74–7.45(m,5H),7.25–7.17(m,2H),6.85–6.77(m,1H),6.56(dd,1H),5.01–4.66(m,2H),4.42–4.28(m,2H),4.16–3.98(m,2H),3.89–3.65(m,2H),3.15–2.55(m,10H),2.20–1.80(m,4H),1.70–1.50(m,2H),1.11–0.92(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.12(s,1H),7.74–7.45(m,5H),7.25–7.17(m,2H),6.85–6.77(m,1H),6.56(dd,1H ),5.01–4.66(m,2H),4.42–4.28(m,2H),4.16–3.98(m,2H),3.89–3.65(m,2H),3.15–2.55(m,10H),2.20–1.80 (m,4H),1.70–1.50(m,2H),1.11–0.92(m,1H).
LCMS m/z＝713.8[M+1]+ LCMS m/z＝713.8[M+1] +
实施例12：制备化合物12
Example 12: Preparation of Compound 12
以化合物12a为原料，参考实施例11得到化合物12(0.10g)得到。Using compound 12a as a raw material, compound 12 (0.10 g) was obtained with reference to Example 11.
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.73–7.48(m,5H),7.31–7.22(m,1H),7.16–7.08(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.43–4.30(m,2H),4.13–3.69(m,4H),3.68–3.07(m,3H),3.05–2.57(m,8H),2.34–1.77(m,5H). 1 H NMR (400MHz, CDCl 3 ) δ8.06(s,1H),7.73–7.48(m,5H),7.31–7.22(m,1H),7.16–7.08(m,1H),6.84–6.77(m ,1H),6.55(dd,1H),4.99–4.89(m,1H),4.43–4.30(m,2H),4.13–3.69(m,4H),3.68–3.07(m,3H),3.05–2.57 (m,8H),2.34–1.77(m,5H).
LCMS m/z＝699.2[M+1]+ LCMS m/z＝699.2[M+1] +
实施例13：制备化合物13
Example 13: Preparation of Compound 13
以化合物13a为原料，参考实施例11得到化合物13(0.16g)得到。Using compound 13a as a raw material, compound 13 (0.16g) was obtained with reference to Example 11.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.72–7.64(m,2H),7.60–7.42(m,3H),7.22–6.96(m,2H),6.86–6.78(m,1H),6.62–6.51(m,1H),5.22–5.11(m,1H),5.00–4.86(m,1H),4.45–4.27(m,2H),4.15–3.96(m,2H),3.92–3.68(m,1H),3.30–2.53(m,9H),2.34–1.64(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ8.12(s,1H),7.72–7.64(m,2H),7.60–7.42(m,3H),7.22–6.96(m,2H),6.86–6.78(m ,1H),6.62–6.51(m,1H),5.22–5.11(m,1H),5.00–4.86(m,1H),4.45–4.27(m,2H),4.15–3.96(m,2H),3.92 –3.68(m,1H),3.30–2.53(m,9H),2.34–1.64(m,7H).
LCMS m/z＝699.2[M+1]+LCMS m/z＝699.2[M+1]+
实施例14：制备化合物14
Example 14: Preparation of Compound 14
以化合物14a为原料，参考实施例1得到化合物14(0.17g)。Using compound 14a as a raw material, compound 14 (0.17g) was obtained with reference to Example 1.
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.72–6.90(m,6H),6.84–6.74(m,1H),6.59–6.49(m,1H),4.99–4.87(m,1H),4.84–4.20(m,4H),4.10–3.95(m,2H),3.92–3.68(m,2H),3.52–3.36(m,1H),3.10–2.63(m,8H),2.54–2.40(m,1H),2.18–1.81(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.00(s,1H),7.72–6.90(m,6H),6.84–6.74(m,1H),6.59–6.49(m,1H),4.99–4.87(m ,1H),4.84–4.20(m,4H),4.10–3.95(m,2H),3.92–3.68(m,2H),3.52–3.36(m,1H),3.10–2.63(m,8H),2.54 –2.40(m,1H),2.18–1.81(m,3H).
LCMS m/z＝685.2[M+1]+ LCMS m/z＝685.2[M+1] +
实施例15：制备化合物15
Example 15: Preparation of Compound 15
以15a和2b为原料，参考实施例1得到化合物15(0.15g)Using 15a and 2b as raw materials, compound 15 (0.15g) was obtained with reference to Example 1
第二步：化合物15的制备Step 2: Preparation of Compound 15
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.69(s,1H),8.63(s,1H),8.37–8.30(m,1H),8.08–8.00(m,1H),7.83–7.72(m,1H),7.72–7.59(m,2H),7.53–7.36(m,3H),6.89–6.78(m,1H),6.69(dd,1H),5.12–5.02(m,1H),4.42–4.28(m,2H),4.04–3.93(m,2H),3.92–3.77(m,1H),3.28–2.98(m,4H),2.97–2.80(m,1H),2.68–2.44(m,2H),2.14–1.84(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.07(s,1H),8.69(s,1H),8.63(s,1H),8.37–8.30(m,1H),8.08–8.00(m,1H) ),7.83–7.72(m,1H),7.72–7.59(m,2H),7.53–7.36(m,3H),6.89–6.78(m,1H),6.69(dd,1H),5.12–5.02(m ,1H),4.42–4.28(m,2H),4.04–3.93(m,2H),3.92–3.77(m,1H),3.28–2.98(m,4H),2.97–2.80(m,1H),2.68 –2.44(m,2H),2.14–1.84(m,3H).
实施例16：制备化合物16
Example 16: Preparation of Compound 16
第一步：16B的制备Step One: Preparation of 16B
向反应瓶中依次加入16A(2.00g,10.15mmol)、环丙基硼酸(1.31g,15.25mmol)、无水磷酸钾(8.62g,40.61mmol)、三环己基膦(1.14g,4.07mmol)和醋酸钯(0.46g,2.05mmol)，氮气氛围加入1,4-二氧六环(25mL)和水(2.5mL)，90℃反应16h。将反应液冷却至室温，加入乙酸乙酯萃取(40mL×3)，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:5)，得16B(1.32g，收率：82％)。Add 16A (2.00g, 10.15mmol), cyclopropylboronic acid (1.31g, 15.25mmol), anhydrous potassium phosphate (8.62g, 40.61mmol), and tricyclohexylphosphine (1.14g, 4.07mmol) to the reaction bottle in sequence. and palladium acetate (0.46g, 2.05mmol), 1,4-dioxane (25mL) and water (2.5mL) were added in a nitrogen atmosphere, and the reaction was carried out at 90°C for 16h. The reaction solution was cooled to room temperature, and extracted with ethyl acetate (40 mL /petroleum ether (v/v)=1:5) to obtain 16B (1.32g, yield: 82%).
LCMS m/z＝159.1[M+1]+ LCMS m/z＝159.1[M+1] +
第二步：16b的制备Step 2: Preparation of 16b
将16a(1.5g，13.87mmol)加入到100mL三口瓶中，加入50％浓硫酸(40mL)，冷却至0℃，缓慢加入N-碘代丁二酰亚胺(4.6g，20.45mmol)，室温反应16h。将反应体系缓慢加入到40mL饱和碳酸钠水溶液中，用乙酸乙酯萃取(80mL×2)，有机相用饱和硫代硫酸钠水溶液洗涤(80mL×2)和饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝81:19)，得16b(2.3g，收率：71％)。Add 16a (1.5g, 13.87mmol) to a 100mL three-necked flask, add 50% concentrated sulfuric acid (40mL), cool to 0°C, slowly add N-iodosuccinimide (4.6g, 20.45mmol), room temperature Reaction 16h. The reaction system was slowly added to 40 mL of saturated aqueous sodium carbonate solution, extracted with ethyl acetate (80 mL × 2), and the organic phase was washed with saturated aqueous sodium thiosulfate solution (80 mL × 2) and saturated aqueous sodium chloride solution (50 mL × 2 ), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 81:19) to obtain 16b (2.3 g, yield: 71%).
LCMS m/z＝235.1[M+1]+ LCMS m/z＝235.1[M+1] +
第三步：16c的制备Step 3: Preparation of 16c
将16b(0.8g，3.42mmol)加入到100mL单口瓶中，加入20mL乙腈，依次加入1-溴环丁烷-1-甲酸乙酯(698mg，3.37mmol)和碳酸铯(2.2g，6.75mmol)，90℃反应3h。将反应液冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝89:11)，得16c(0.9g，收率：73％)。Add 16b (0.8g, 3.42mmol) into a 100mL single-neck bottle, add 20mL acetonitrile, and add 1-bromocyclobutane-1-carboxylic acid ethyl ester (698mg, 3.37mmol) and cesium carbonate (2.2g, 6.75mmol) in sequence. , react at 90°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 89:11) to obtain 16c (0.9g, yield: 73 %).
LCMS m/z＝361.1[M+1]+ LCMS m/z＝361.1[M+1] +
第四步：16d的制备Step 4: Preparation of 16d
将16c(0.9g，2.5mmol)溶于15mL四氢呋喃中，加入5mL水，冷却至0℃，加入一水合氢氧化锂(315mg，7.51mmol)，室温反应2h。将反应液用0.5mol/L盐酸调pH至4，用乙酸乙酯萃取(60mL×3)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩， 粗品用硅胶色谱柱分离纯化(二氯甲烷:甲醇(v/v)＝95:5)，得粗品(0.6g)。将上述粗品(200mg)加入到50mL单口瓶中，加入15mL二氯甲烷，加入1-氯-N，N，2-三甲基丙烯胺(120mg，0.9mmol)，室温反应1h后，依次加入三乙胺(182mg，1.8mmol)和16B(95mg，0.6mmol)，室温反应1h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝85:15)，得16d(120mg，收率：42％)。Dissolve 16c (0.9g, 2.5mmol) in 15mL tetrahydrofuran, add 5mL water, cool to 0°C, add lithium hydroxide monohydrate (315mg, 7.51mmol), and react at room temperature for 2h. Adjust the pH of the reaction solution to 4 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (60 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (60 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (dichloromethane: methanol (v/v) = 95:5) to obtain a crude product (0.6g). Add the above crude product (200 mg) into a 50 mL single-neck bottle, add 15 mL dichloromethane, add 1-chloro-N, N, 2-trimethylpropenylamine (120 mg, 0.9 mmol), react at room temperature for 1 hour, and then add three Ethylamine (182 mg, 1.8 mmol) and 16B (95 mg, 0.6 mmol) were reacted at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 85:15) to obtain 16d (120 mg, yield: 42%).
LCMS m/z＝473.1[M+1]+ LCMS m/z＝473.1[M+1] +
第五步；化合物16的制备Step 5; Preparation of compound 16
将16d(120mg，0.25mmol)加入到50mL单口瓶中，加入DMF(10mL)，加入粗品中间体1(126mg)、TEA(76mg，0.75mmol)、PdCl2(PPh3)2(17mg，0.024mmol)和CuI(10mg，0.053mmol)，置换氮气三次，50℃反应2h，将反应体系冷却至室温，加入饱和氯化铵水溶液(120mL)，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝37:63)，得化合物16(90mg，收率：53％)。Add 16d (120mg, 0.25mmol) to a 50mL single-neck bottle, add DMF (10mL), add crude intermediate 1 (126mg), TEA (76mg, 0.75mmol), PdCl 2 (PPh 3 ) 2 (17mg, 0.024mmol) ) and CuI (10 mg, 0.053 mmol), replace nitrogen three times, react at 50°C for 2 hours, cool the reaction system to room temperature, add saturated aqueous ammonium chloride solution (120 mL), extract with ethyl acetate (50 mL × 3), use the organic phase Wash with saturated aqueous sodium chloride solution (60mL (90 mg, yield: 53%).
1H NMR(400MHz,CDCl3)δ8.53(s,1H),8.40(d,1H),7.94(s,1H),7.67(d,1H),7.59(s,1H),7.49(dd,1H),7.37–7.32(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.44–4.30(m,2H),4.10–4.00(m,2H),3.88–3.76(m,1H),3.10–2.60(m,7H),2.30–1.90(m,4H),1.53–1.40(m,1H),1.06–0.81(m,6H),0.59–0.50(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.53(s,1H),8.40(d,1H),7.94(s,1H),7.67(d,1H),7.59(s,1H),7.49(dd, 1H),7.37–7.32(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.44–4.30(m,2H),4.10–4.00( m,2H),3.88–3.76(m,1H),3.10–2.60(m,7H),2.30–1.90(m,4H),1.53–1.40(m,1H),1.06–0.81(m,6H), 0.59–0.50(m,2H).
LCMS m/z＝680.1[M-1]- LCMS m/z＝680.1[M-1] -
实施例17：化合物17的制备
Example 17: Preparation of Compound 17
以化合物17B和16c为原料，参照实施例16的合成方法得到化合物17(60mg)Using compounds 17B and 16c as raw materials, compound 17 (60 mg) was obtained by referring to the synthesis method of Example 16.
1H NMR(400MHz,CDCl3)δ8.44(d,1H),8.31(s,1H),7.93(s,1H),7.73–7.45(m,4H),6.84–6.77(m,1H),6.56(dd,1H),4.98–4.87(m,1H),4.44–4.30(m,2H),4.10–3.97(m,2H),3.90–3.76(m,1H),3.07–2.61(m,7H),2.26–1.94(m,7H),1.11–1.03(m,2H),1.01–0.93(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.44(d,1H),8.31(s,1H),7.93(s,1H),7.73–7.45(m,4H),6.84–6.77(m,1H), 6.56(dd,1H),4.98–4.87(m,1H),4.44–4.30(m,2H),4.10–3.97(m,2H),3.90–3.76(m,1H),3.07–2.61(m,7H ),2.26–1.94(m,7H),1.11–1.03(m,2H),1.01–0.93(m,2H).
LCMS m/z＝723.8[M+1]+ LCMS m/z＝723.8[M+1] +
实施例18：化合物18的制备
Example 18: Preparation of Compound 18
第一步：18b的制备Step 1: Preparation of 18b
将18a(5.0g，30.1mmol)、4-氟-1H-吡唑(4.11g，47.75mmol)和碳酸钾(6.60g，47.76mmol)加入80mL DMF中，80℃反应16h。将反应液冷却到室温，加入100mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到18b(4.0g，收率：57％)。Add 18a (5.0g, 30.1mmol), 4-fluoro-1H-pyrazole (4.11g, 47.75mmol) and potassium carbonate (6.60g, 47.76mmol) into 80mL DMF and react at 80°C for 16h. The reaction solution was cooled to room temperature, 100 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v)=3:1), 18b (4.0 g, yield: 57%) was obtained.
第二步：18c的制备Step 2: Preparation of 18c
将18b(1.5g，6.46mmol)溶于30mL甲醇中，加入0.2g 10％Pd/C，置换氢气三次，置于氢气球氛围下室温反应2h。将反应体系过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得粗品18c(0.8g)。Dissolve 18b (1.5g, 6.46mmol) in 30mL methanol, add 0.2g 10% Pd/C, replace the hydrogen three times, and react at room temperature for 2 hours under a hydrogen balloon atmosphere. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain crude product 18c (0.8g).
LCMS m/z＝203.1[M+1]+ LCMS m/z＝203.1[M+1] +
第三步：18d的制备Step 3: Preparation of 18d
将上述粗品18c(0.4g)与2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸(0.67g，2.39mmol)溶于15mL DCM中，加入TCFH(0.83g，2.96mmol)，缓慢滴加N-甲基咪唑(0.65g，7.92mmol)，室温反应16h。将反应体系减压浓缩，粗品用50mL二氯甲烷溶解，有机相用20mL水洗涤，无水硫酸干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到18d(0.78g，收率：70％)。Dissolve the above crude product 18c (0.4g) and 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid (0.67g, 2.39mmol) in 15mL DCM, add TCFH (0.83 g, 2.96mmol), slowly add N-methylimidazole (0.65g, 7.92mmol) dropwise, and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was dissolved in 50 mL of methylene chloride. The organic phase was washed with 20 mL of water, dried with anhydrous sulfuric acid, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) =5:1), obtaining 18d (0.78g, yield: 70%).
LCMS m/z＝465.4[M+1]+ LCMS m/z＝465.4[M+1] +
第四步：化合物18的制备Step 4: Preparation of Compound 18
将18d(0.23g，0.50mmol)、中间体1(0.25g)、TEA(0.15g，1.48mmol)、CuI(10mg，0.0525mmol)和PdCl2(PPh3)2(35mg，0.0499mmol)加入5mL DMF，氮气氛围50℃反应1h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物18(0.05g，收率：15％)。18d (0.23g, 0.50mmol), intermediate 1 (0.25g), TEA (0.15g, 1.48mmol), CuI (10mg, 0.0525mmol) and PdCl 2 (PPh 3 ) 2 (35mg, 0.0499mmol) were added to 5mL DMF, react in nitrogen atmosphere at 50°C for 1 hour. Cool the reaction solution to room temperature, add 50 mL of water, and suction filter. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/petroleum ether/ Ethyl acetate (v/v)=1:1) to obtain compound 18 (0.05g, yield: 15%).
1H NMR(400MHz,CDCl3)δ10.29(s,1H),8.72(d,1H),8.02(s,1H),7.74(s,1H),7.72–7.65(m,1H),7.65–7.58(m,3H),7.56–7.52(m,1H),7.50–7.46(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.45–4.34(m,2H),4.17–4.04(m,2H),3.92–3.78(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H),1.88(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ10.29(s,1H),8.72(d,1H),8.02(s,1H),7.74(s,1H),7.72–7.65(m,1H),7.65– 7.58(m,3H),7.56–7.52(m,1H),7.50–7.46(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H), 4.45–4.34(m,2H),4.17–4.04(m,2H),3.92–3.78(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H),1.88(s,6H ).
LCMS m/z＝674.3[M+1]+ LCMS m/z＝674.3[M+1] +
实施例19：化合物19的制备
Example 19: Preparation of Compound 19
以化合物19b和2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸为原料，参照实施例18的合成方法得到化合物19(0.33g)Using compound 19b and 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw materials, compound 19 (0.33g) was obtained by referring to the synthesis method of Example 18.
1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.49(d,1H),8.05(s,1H),7.80(s,1H),7.74(s,1H), 7.67(d,1H),7.59–7.54(m,1H),7.54–7.47(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.95–2.65(m,3H),2.22–2.06(m,4H),1.93(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.98(s,1H),8.49(d,1H),8.05(s,1H),7.80(s,1H),7.74(s,1H), 7.67(d,1H),7.59–7.54(m,1H),7.54–7.47(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H), 4.40–4.30(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.95–2.65(m,3H),2.22–2.06(m,4H),1.93(s,6H ).
LCMS m/z＝628.6[M+1]+ LCMS m/z＝628.6[M+1] +
实施例20：化合物20的制备
Example 20: Preparation of Compound 20
以化合物20b为原料，参考实施例18得到化合物20(0.02g)。Using compound 20b as a raw material, compound 20 (0.02g) was obtained with reference to Example 18.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.77(s,1H),7.74–7.64(m,3H),7.61(s,1H),7.50–7.44(m,1H),6.84–6.77(m,1H),6.56(dd,1H),5.48(q,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.15–4.03(m,2H),3.89–3.76(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.98(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.91(s,1H),7.77(s,1H),7.74–7.64(m,3H),7.61(s,1H),7.50–7.44(m,1H), 6.84–6.77(m,1H),6.56(dd,1H),5.48(q,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.15–4.03(m,2H), 3.89–3.76(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.98(s,6H).
LCMS m/z＝725.2[M+1]+ LCMS m/z＝725.2[M+1] +
实施例21：化合物21的制备
Example 21: Preparation of Compound 21
以化合物21a为原料，参考实施例19得到化合物21(0.20g)。Using compound 21a as a raw material, compound 21 (0.20 g) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.43(d,1H),8.08(s,1H),7.78(s,1H),7.71(s,1H),7.67(d,1H),7.62–7.56(m,1H),7.47(dd,1H),6.83–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.96–2.64(m,4H),2.17–2.07(m,1H),1.94(s,6H),1.33(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.95(s,1H),8.43(d,1H),8.08(s,1H),7.78(s,1H),7.71(s,1H),7.67(d, 1H),7.62–7.56(m,1H),7.47(dd,1H),6.83–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m, 2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.96–2.64(m,4H),2.17–2.07(m,1H),1.94(s,6H),1.33(d, 6H).
LCMS m/z＝699.2[M+1]+ LCMS m/z＝699.2[M+1] +
实施例22：化合物22的制备
Example 22: Preparation of Compound 22
参考化合物17的制备方法，得到化合物22(85mg)Referring to the preparation method of compound 17, compound 22 (85 mg) was obtained
1H NMR(400MHz,CDCl3)δ8.37–8.22(m,2H),8.03(br.s,1H),7.81–7.61(m,3H),7.36–7.28(m,1H),7.22–7.12(m,1H),6.85–6.74(m,1H),6.55(dd,1H),4.99–4.87(m,1H),4.42–4.28(m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),3.45–3.30(m,2H),3.15–3.00(m,2H),2.97–2.65 (m,5H),2.28–1.95(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ8.37–8.22(m,2H),8.03(br.s,1H),7.81–7.61(m,3H),7.36–7.28(m,1H),7.22–7.12 (m,1H),6.85–6.74(m,1H),6.55(dd,1H),4.99–4.87(m,1H),4.42–4.28(m,2H),4.12–4.00(m,2H),3.88 –3.72(m,1H),3.45–3.30(m,2H),3.15–3.00(m,2H),2.97–2.65 (m,5H),2.28–1.95(m,9H).
LCMS m/z＝668.3[M+1]+ LCMS m/z＝668.3[M+1] +
实施例23：化合物23的三氟乙酸盐的制备
Example 23: Preparation of trifluoroacetate salt of compound 23
第一步：23B的制备Step One: Preparation of 23B
将23A(2.8g，10.02mmol)(合成方法见WO2019074962)、3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(2.17g，11.97mmol)、TEA(3.04g，30.04mmol)、CuI(190mg，1.00mmol)和PdCl2(PPh3)2(700mg，1.00mmol)加入60mL二氯甲烷，氮气氛围室温反应18h。向反应体系中加入150mL水，用1mol/L盐酸调体系pH至2，用100mL二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝20:1)，得到23B(3.3g，收率：99％)。23A (2.8g, 10.02mmol) (see WO2019074962 for the synthesis method), tert-butyl 3-ethynylazetidine-1-carboxylate (2.17g, 11.97mmol), TEA (3.04g, 30.04mmol), CuI (190 mg, 1.00 mmol) and PdCl 2 (PPh 3 ) 2 (700 mg, 1.00 mmol) were added with 60 mL of methylene chloride, and the reaction was carried out at room temperature in a nitrogen atmosphere for 18 h. Add 150 mL of water to the reaction system, adjust the pH of the system to 2 with 1 mol/L hydrochloric acid, extract with 100 mL of dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (dichloromethane/methanol ( v/v)=20:1), 23B (3.3g, yield: 99%) was obtained.
LCMS m/z＝334.5[M+1]+。LCMS m/z=334.5[M+1] + .
第二步：23d的制备Step 2: Preparation of 23d
将23c(0.15g，1.00mmol)与23B(0.40g，1.20mmol)溶于15mL DCM中，加入TCFH(0.42g，1.50mmol)，缓慢滴加N-甲基咪唑(0.33g，4.02mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到23d(0.2g，收率：43％)。Dissolve 23c (0.15g, 1.00mmol) and 23B (0.40g, 1.20mmol) in 15mL DCM, add TCFH (0.42g, 1.50mmol), slowly add N-methylimidazole (0.33g, 4.02mmol), React at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 23d (0.2 g, yield: 43%).
第三步：23e的对甲苯磺酸盐的制备Step 3: Preparation of p-toluenesulfonate of 23e
将23d(200mg,0.43mmol)溶于4mL乙腈中，加入一水合对甲苯磺酸(0.22g，1.05mmol)，室温反应2h。将反应液减压浓缩，得粗品23e的对甲苯磺酸盐(0.44g)。Dissolve 23d (200 mg, 0.43 mmol) in 4 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.22 g, 1.05 mmol), and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude product 23e p-toluenesulfonate (0.44g).
LCMS m/z＝367.4[M+1]+ LCMS m/z＝367.4[M+1] +
第四步：化合物23的三氟乙酸盐的制备Step 4: Preparation of trifluoroacetate salt of compound 23
将上述粗品23e的对甲苯磺酸盐(0.44g)溶于5mL DMSO中，加入DIPEA(0.34g，2.63mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(0.12g，0.43mmol)，80℃反应3h。将反应液冷却至室温，加入40mL水，过滤，滤饼用10mL水洗涤，将滤饼用50mL DCM溶解，无水硫酸钠干燥，减压浓缩后粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得到化合物23的三氟乙酸盐(0.05g)。Dissolve the p-toluenesulfonate salt (0.44g) of the above crude product 23e in 5mL DMSO, add DIPEA (0.34g, 2.63mmol) and 2-(2,6-dioxopiperidin-3-yl)-5- Fluoroisoindoline-1,3-dione (0.12g, 0.43mmol), react at 80°C for 3 hours. Cool the reaction solution to room temperature, add 40 mL of water, filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 50 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure and pass the crude product through Pre-HPLC (instrument and preparation column: use Glison GX-281 preparation liquid phase, preparation column model is Sunfire C18, 5μm, inner diameter × length = 30mm × 150mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 23 (0.05g).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.01(s,1H),8.30(s,1H),7.87–7.77(m,2H),7.68(d,1H),7.63–7.58(m,1H),7.44(dd,1H),6.90–6.84(m,1H),6.71(dd,1H),5.11–5.02(m,1H),4.45–4.32(m,2H),4.28(s,1H),4.06–3.96(m,2H),3.95–3.83(m,1H),2.95–2.80(m,1H),2.71–2.51(m,2H),2.08–1.95(m,1H),1.84(s,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),9.01(s,1H),8.30(s,1H),7.87–7.77(m,2H),7.68(d,1H), 7.63–7.58(m,1H),7.44(dd,1H),6.90–6.84(m,1H),6.71(dd,1H),5.11–5.02(m,1H),4.45–4.32(m,2H), 4.28(s,1H),4.06–3.96(m,2H),3.95–3.83(m,1H),2.95–2.80(m,1H),2.71–2.51(m,2H),2.08–1.95(m,1H ),1.84(s,6H).
LCMS m/z＝623.1[M+1]+ LCMS m/z＝623.1[M+1] +
实施例24：化合物24的制备
Example 24: Preparation of Compound 24
以24b和2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸为原料,参考化合物18的制备方法，得到化合物24(0.05g).Using 24b and 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw materials and referring to the preparation method of compound 18, compound 24 (0.05g) was obtained.
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.33(d,1H),8.00(s,1H),7.86–7.76(m,2H),7.67(d,1H),7.62–7.56(m,1H),7.56–7.45(m,1H),6.83–6.76(m,1H),6.54(dd,1H),4.98–4.87(m,1H),4.40–4.30(m,2H),4.10–4.00(m,2H),3.86–3.72(m,1H),2.95–2.64(m,3H),2.18–2.08(m,1H),1.97(s,6H),1.69(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.12(s,1H),8.33(d,1H),8.00(s,1H),7.86–7.76(m,2H),7.67(d,1H),7.62– 7.56(m,1H),7.56–7.45(m,1H),6.83–6.76(m,1H),6.54(dd,1H),4.98–4.87(m,1H),4.40–4.30(m,2H), 4.10–4.00(m,2H),3.86–3.72(m,1H),2.95–2.64(m,3H),2.18–2.08(m,1H),1.97(s,6H),1.69(s,6H).
实施例25：化合物25的制备
Example 25: Preparation of Compound 25
第一步：25c的制备Step One: Preparation of 25c
将25b(1.5g，5.10mmol)溶于20mL四氢呋喃中，冷却至-78℃，缓慢滴加LDA的四氢呋喃/正己烷(v/v)＝12:25溶液(2.0mol/L)(3.05mL，6.10mmol)，-78℃反应30min后，加入溴甲基环丙烷(1.38g，10.2mmol)，升至室温反应3h。向反应液中加入40mL饱和氯化钠溶液洗涤，用60mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到25c(288mg，收率：16％)。Dissolve 25b (1.5g, 5.10mmol) in 20mL tetrahydrofuran, cool to -78°C, slowly add LDA solution of tetrahydrofuran/n-hexane (v/v) = 12:25 (2.0mol/L) (3.05mL, 6.10 mmol), reacted at -78°C for 30 min, then added bromomethylcyclopropane (1.38g, 10.2 mmol), and raised to room temperature for 3 h. Add 40 mL of saturated sodium chloride solution to the reaction solution for washing, and extract with 60 mL of ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/ v)=5:1), 25c (288 mg, yield: 16%) was obtained.
以25c和2-氯-4-(三氟甲基)苯胺为原料，参考实施例5得到化合物25(81mg)。Using 25c and 2-chloro-4-(trifluoromethyl)aniline as raw materials, compound 25 (81 mg) was obtained with reference to Example 5.
1H NMR(400MHz,CDCl3)δ9.64(s,1H),8.55–8.47(m,1H),7.99(s,1H),7.86–7.76(m,2H),7.71–7.63(m,1H),7.62–7.57(m,1H),7.53–7.45(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.15–4.00(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.50–2.35(m,1H),2.20–2.05(m,2H),2.00(s,3H),0.60–0.30(m,3H),0.20–0.07(m,1H),0.02–-0.10(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ9.64(s,1H),8.55–8.47(m,1H),7.99(s,1H),7.86–7.76(m,2H),7.71–7.63(m,1H ),7.62–7.57(m,1H),7.53–7.45(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.44–4.30(m ,2H),4.15–4.00(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.50–2.35(m,1H),2.20–2.05(m,2H),2.00 (s,3H),0.60–0.30(m,3H),0.20–0.07(m,1H),0.02–-0.10(m,1H).
LCMS m/z＝707.6[M+1]+ LCMS m/z＝707.6[M+1] +
实施例26：制备化合物26的三氟乙酸盐
Example 26: Preparation of trifluoroacetate salt of compound 26
第一步：26c的制备Step One: Preparation of 26c
将60％氢化钠(2.45g)加入到300mL DMSO中，冷却至0℃，将40mL叔丁基((1,3-二溴丙-2-基)氧基)二苯基硅烷(20.4g，44.7mmol)(合成方法见WO2013173720)和26b(10.5g，34.08mmol)的DMSO溶液滴加到上述溶液中，室温反应12h。向反应体系中加入1L纯化水，用300mL乙酸乙酯萃取，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝4:1)，得26c(3.5g，收率：17％)。Add 60% sodium hydride (2.45g) to 300mL DMSO, cool to 0°C, add 40mL tert-butyl ((1,3-dibromoprop-2-yl)oxy)diphenylsilane (20.4g, The DMSO solution of 44.7 mmol) (see WO2013173720 for the synthesis method) and 26b (10.5 g, 34.08 mmol) was dropwise added to the above solution, and the reaction was carried out at room temperature for 12 h. Add 1 L of purified water to the reaction system, extract with 300 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) =4:1), 26c (3.5g, yield: 17%) was obtained.
LCMS m/z＝603.2[M+1]+。LCMS m/z=603.2[M+1] + .
第二步：26d的制备Step 2: Preparation of 26d
将26c(3.5g,5.81mmol)加入60mL二氯甲烷中，加入20mL三氟乙酸，室温反应3h。将反应液减压浓缩，加入100mL二氯甲烷，用饱和碳酸钠水溶液调pH至9，再用2mol/L盐酸调pH至5，分离出有机相，无水硫酸钠干燥，减压浓缩，得粗品(2.5g)。将上述粗品(2.5g)与2-氯-4-(三氟甲基)苯胺(0.88g，4.5mmol)溶于100mL DCM中，加入TCFH(1.96g，7.0mmol)，缓慢滴加N-甲基咪唑(1.5g，18.27mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到26d(2.3g，收率：71％)。Add 26c (3.5g, 5.81mmol) to 60mL dichloromethane, add 20mL trifluoroacetic acid, and react at room temperature for 3h. Concentrate the reaction solution under reduced pressure, add 100 mL of methylene chloride, adjust the pH to 9 with saturated aqueous sodium carbonate solution, and then adjust the pH to 5 with 2 mol/L hydrochloric acid. Separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Crude product (2.5g). Dissolve the above crude product (2.5g) and 2-chloro-4-(trifluoromethyl)aniline (0.88g, 4.5mmol) in 100mL DCM, add TCFH (1.96g, 7.0mmol), and slowly add N-methyl Imidazole (1.5g, 18.27mmol), reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 26d (2.3 g, yield: 71%).
第三步：26e的制备Step 3: Preparation of 26e
将26d(2.3g，3.2mmol)溶于60mL THF中，加入TBAF(2.6g，9.94mmol)，回流反应5h。将反应体系冷却至室温，减压浓缩，向残留物中加入50mL乙酸乙酯，有机相用100mL纯化水洗涤，无水硫酸钠干燥，减压浓缩，得26e(0.6g，收率：39.0％)。Dissolve 26d (2.3g, 3.2mmol) in 60mL THF, add TBAF (2.6g, 9.94mmol), and reflux for 5h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 50 mL of ethyl acetate was added to the residue, the organic phase was washed with 100 mL of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 26e (0.6 g, yield: 39.0% ).
LCMS m/z＝485.9[M+1]+。LCMS m/z=485.9[M+1] + .
第四步：化合物26的三氟乙酸盐的制备Step 4: Preparation of trifluoroacetate salt of compound 26
将26e(0.1g，0.21mmol)、中间体1(0.1g，0.3mmol)、TEA(0.1g，1.0mmol)、CuI(3.6mg，0.019mmol)和PdCl2(PPh3)2(14mg，0.02mmol)加入5mL DMF，氮气氛围60℃反应3h。将反应液冷却至室温，过滤，将反应液过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得化合物26的三氟乙酸盐(0.08g)。26e (0.1g, 0.21mmol), intermediate 1 (0.1g, 0.3mmol), TEA (0.1g, 1.0mmol), CuI (3.6mg, 0.019mmol) and PdCl 2 (PPh 3 ) 2 (14mg, 0.02 mmol), add 5 mL DMF, and react at 60°C for 3 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and passed through Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 26 (0.08g).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.05–8.91(m,1H),8.48–8.27(m,1H),8.23–8.12(m,1H),7.94–7.84(m,2H),7.78–7.64(m,2H),6.90–6.83(m,1H),6.76–6.67(m,1H),5.11–5.01(m,1H),4.45–4.32(m,2H),4.28–4.07(m,1H),4.05–3.95(m,2H),3.95–3.83(m,1H),3.28–3.05(m,2H),2.97–2.70(m,2H),2.65–2.51(m,3H),2.08–1.95(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),9.05–8.91(m,1H),8.48–8.27(m,1H),8.23–8.12(m,1H),7.94–7.84 (m,2H),7.78–7.64(m,2H),6.90–6.83(m,1H),6.76–6.67(m,1H),5.11–5.01(m,1H),4.45–4.32(m,2H) ,4.28–4.07(m,1H),4.05–3.95(m,2H),3.95–3.83(m,1H),3.28–3.05(m,2H),2.97–2.70(m,2H),2.65–2.51( m,3H),2.08–1.95(m,1H).
LCMS m/z＝695.2[M+1]+ LCMS m/z＝695.2[M+1] +
实施例27：化合物27的三氟乙酸盐的制备
Example 27: Preparation of trifluoroacetate salt of compound 27
第一步：27b的制备Step One: Preparation of 27b
将27a(2.7g，10mmol)、(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(3.0g，15.15mmol)、Pd(dppf)Cl2(725.7mg，1.0mmol)和CsF(4.6g，30.28mmol)加入80mL 1,4-二氧六环和20mL水中，85℃反应12h。将反应体系冷却至室温，减压浓缩，加入100mL乙酸乙酯，用100mL纯化水洗涤，分离出有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝10:1)，得27b(2.3g，收率：88％)。27a (2.7g, 10mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3.0g, 15.15mmol), Pd(dppf)Cl 2 (725.7mg, 1.0mmol) and CsF (4.6g, 30.28mmol) were added to 80mL 1,4-dioxane and 20mL water, and reacted at 85°C for 12h. Cool the reaction system to room temperature, concentrate under reduced pressure, add 100 mL of ethyl acetate, wash with 100 mL of purified water, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum Ether:ethyl acetate (v/v)=10:1), to obtain 27b (2.3g, yield: 88%).
第二步：27c的制备Step 2: Preparation of 27c
将27b(2.3g，8.81mmol)加入50mL四氢呋喃中，加入4mL浓盐酸，室温反应16h。将反应液减压浓缩，加入100mL二氯甲烷，用饱和碳酸钠水溶液调pH至10，分离出有机相，无水硫酸钠干燥，减压浓缩，得粗品27c(1.5g)。Add 27b (2.3g, 8.81mmol) to 50mL tetrahydrofuran, add 4mL concentrated hydrochloric acid, and react at room temperature for 16h. The reaction solution was concentrated under reduced pressure, 100 mL of methylene chloride was added, and the pH was adjusted to 10 with saturated aqueous sodium carbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 27c (1.5 g).
第三步：27d的制备Step 3: Preparation of 27d
将上述粗品27c(1.5g)溶于30mL甲醇中，加入碳酸钾(2.0g，14.47mmol)，冷却至0℃，滴入(1-重氮基-2-氧代丙基)膦酸二甲酯(1.93g，10mmol)，置换氮气三次，室温反应16h。将反应体系减压浓缩，加入100mL乙酸乙酯，用100mL水洗涤，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝4:1)，得27d(0.47g，从化合物27b算两步收率：23％)。Dissolve the above crude product 27c (1.5g) in 30mL methanol, add potassium carbonate (2.0g, 14.47mmol), cool to 0°C, and drop (1-diazo-2-oxopropyl)phosphonic acid dimethyl The ester (1.93g, 10mmol) was replaced with nitrogen three times, and the reaction was carried out at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, 100 mL of ethyl acetate was added, washed with 100 mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/ v)=4:1), to obtain 27d (0.47g, two-step yield calculated from compound 27b: 23%).
第四步：27e的制备Step 4: Preparation of 27e
将27d(0.47g，2.05mmol)加入到8mL乙醇中，加入还原铁粉(0.56g，10mmol)和2mL饱和氯化铵水溶液，回流反应2h。将反应体系冷却至室温，减压浓缩，加入40mL乙酸乙酯，用40mL水洗涤，分离出有机相，无水硫酸钠干燥，减压浓缩，得粗品27e(0.36g)。Add 27d (0.47g, 2.05mmol) to 8mL of ethanol, add reduced iron powder (0.56g, 10mmol) and 2mL of saturated ammonium chloride aqueous solution, and reflux for 2h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 40 mL of ethyl acetate was added, washed with 40 mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 27e (0.36 g).
LCMS m/z＝200.1[M+1]+ LCMS m/z＝200.1[M+1] +
化合物27的三氟乙酸盐以化合物27e+23B为原料，参考实施例23制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物27的三氟乙酸盐(50mg)。The trifluoroacetate of compound 27 was prepared using compound 27e+23B as raw materials, with reference to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetate of compound 27. Acetate (50mg).
1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.47(d,1H),8.09(s,1H),7.81(s,1H),7.75(s,1H),7.67(d,1H),7.59–7.43(m,2H),6.83–6.78(m,1H),6.55(dd,1H),4.98–4.90(m,1H),4.42–4.30(m,2H),4.11–4.00(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.08(m,4H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.83(s,1H),8.47(d,1H),8.09(s,1H),7.81(s,1H),7.75(s,1H),7.67(d, 1H),7.59–7.43(m,2H),6.83–6.78(m,1H),6.55(dd,1H),4.98–4.90(m,1H),4.42–4.30(m,2H),4.11–4.00( m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.08(m,4H),1.94(s,6H).
实施例28：化合物28的制备
Example 28: Preparation of Compound 28
第一步：28B的制备Step One: Preparation of 28B
向反应瓶中分别加入28A(5.00g,24.15mmol)、2mol/L氢氧化钠水溶液(25mL)和25mL乙醇，室温搅拌2h。将反应液冷却至0℃，加入1mol/L盐酸调pH值至2，用乙酸乙酯萃取(50mL×3)，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到粗品(4.6g)。向上述粗品(4.6g)加入1-氯-N,N,2-三甲基丙烯胺(5.14g,38.55mmol)和DCM(100mL)，室温搅拌1h后，加入TEA(10.67mL,76.55mmol)和2-氯-4-三氟甲基苯胺(5.02g,25.67mmol)，室温反应16h。将反应液减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:5)，得到28B(6.05g，收率：70％)。Add 28A (5.00g, 24.15mmol), 2mol/L sodium hydroxide aqueous solution (25mL) and 25mL ethanol to the reaction flask respectively, and stir at room temperature for 2h. Cool the reaction solution to 0°C, add 1 mol/L hydrochloric acid to adjust the pH to 2, extract with ethyl acetate (50 mL × 3), wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , to obtain crude product (4.6g). 1-Chloro-N,N,2-trimethylpropenylamine (5.14g, 38.55mmol) and DCM (100mL) were added to the above crude product (4.6g). After stirring at room temperature for 1 hour, TEA (10.67mL, 76.55mmol) was added. And 2-chloro-4-trifluoromethylaniline (5.02g, 25.67mmol), react at room temperature for 16h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:5) to obtain 28B (6.05 g, yield: 70%).
第二步：28b的制备Step 2: Preparation of 28b
将28a(5.0g，39.64mmol)溶于25mL三氟乙酸中，加入N-碘代丁二酰亚胺(9.82g，43.65mmol)，室温反应16h。将反应体系减压浓缩，将残留物缓慢滴加到100mL饱和碳酸氢钠水溶液中，析出产物，过滤，收集滤饼，滤饼用20mL水洗涤，减压干燥，得粗品28b(4.0g，收率：40％)。Dissolve 28a (5.0g, 39.64mmol) in 25mL trifluoroacetic acid, add N-iodosuccinimide (9.82g, 43.65mmol), and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the residue was slowly added dropwise to 100 mL of saturated aqueous sodium bicarbonate solution to precipitate the product, filtered, and the filter cake was collected. The filter cake was washed with 20 mL of water and dried under reduced pressure to obtain crude product 28b (4.0 g, collected rate: 40%).
LCMS m/z＝252.9[M+1]+ LCMS m/z＝252.9[M+1] +
第三步：28c的制备Step 3: Preparation of 28c
将上述粗品28b(1.0g)与28B(1.7g，4.77mmol)溶于25mL乙腈中，加入碳酸铯(2.59g，7.95mmol)，50℃反应6h。将反应体系冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1)，得28c(350mg，收率：14％)。Dissolve the above crude products 28b (1.0g) and 28B (1.7g, 4.77mmol) in 25mL acetonitrile, add cesium carbonate (2.59g, 7.95mmol), and react at 50°C for 6 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 28c (350 mg, yield: 14% ).
LCMS m/z＝528.4[M+1]+ LCMS m/z＝528.4[M+1] +
第四步：28d的制备Step 4: Preparation of 28d
将28c(110mg，0.21mmol)溶于3mL DMF中，加入3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(57mg,0.31mmol)和TEA(64mg,0.63mmol)、CuI(5mg,0.026mmol)和PdCl2(PPh3)2(15mg，0.021mmol)，置换氮气三次，50℃反应2h。将反应液冷却至室温，加入10mL水，用30mL乙酸乙酯萃取，有机相用20mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)，得粗品28d(0.12g)。Dissolve 28c (110 mg, 0.21 mmol) in 3 mL DMF, add 3-ethynyl azetidine-1-carboxylic acid tert-butyl ester (57 mg, 0.31 mmol) and TEA (64 mg, 0.63 mmol), CuI (5 mg, 0.026mmol) and PdCl 2 (PPh 3 ) 2 (15 mg, 0.021mmol), replaced with nitrogen three times, and reacted at 50°C for 2 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, and extracted with 30 mL of ethyl acetate. The organic phase was washed with 20 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v)=3:1), and the crude product 28d (0.12g) was obtained.
第五步：28e的制备 Step 5: Preparation of 28e
将粗品28d(120mg)溶于5mL四氢呋喃与1mL水中，加入一水合氢氧化锂(27mg，0.64mmol)，室温反应3h。将反应体系用2mol/L盐酸调pH至3，用50mL DCM萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得粗品28e(0.12g)。Dissolve crude product 28d (120 mg) in 5 mL tetrahydrofuran and 1 mL water, add lithium hydroxide monohydrate (27 mg, 0.64 mmol), and react at room temperature for 3 h. Adjust the pH of the reaction system to 3 with 2mol/L hydrochloric acid, extract with 50mL DCM, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (dichloromethane/methanol (v/v) = 15:1), and the crude product 28e (0.12g) was obtained.
第六步：28f的对甲苯磺酸盐的制备Step 6: Preparation of 28f p-toluenesulfonate
将粗品28e(120mg)溶于4mL乙腈中，加入一水合对甲苯磺酸(0.16g，0.84mmol)，室温反应2h。将反应液减压浓缩，得粗品28f的对甲苯磺酸盐(300mg)。Dissolve crude product 28e (120 mg) in 4 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.16 g, 0.84 mmol), and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude product 28f p-toluenesulfonate (300 mg).
LCMS m/z＝467.1[M+1]+ LCMS m/z＝467.1[M+1] +
第七步：化合物28的制备Step 7: Preparation of compound 28
将粗品28f的对甲苯磺酸盐(300mg)溶于5mL DMSO中，加入0.25mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(100mg，0.36mmol)，80℃反应3h。将反应液冷却至室温，加入50mL水，过滤，收集滤饼，滤饼用10mL水洗涤，将滤饼用30mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得化合物28(15mg，收率：6％)。Dissolve crude 28f p-toluenesulfonate (300mg) in 5mL DMSO, add 0.25mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1 , 3-diketone (100mg, 0.36mmol), react at 80°C for 3h. Cool the reaction solution to room temperature, add 50 mL of water, filter, collect the filter cake, wash the filter cake with 10 mL of water, dissolve the filter cake with 30 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column ( Dichloromethane/methanol (v/v)=15:1), compound 28 (15 mg, yield: 6%) was obtained.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.57(s,1H),8.45(s,1H),7.98–7.87(m,2H),7.78–7.65(m,2H),6.92–6.87(m,1H),6.80–6.71(m,2H),5.11–5.02(m,1H),4.43–4.30(m,2H),4.24–4.12(m,2H),4.08–3.96(m,1H),3.12–2.97(m,2H),2.97–2.80(m,3H),2.72–2.50(m,2H),2.10–1.95(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),9.57(s,1H),8.45(s,1H),7.98–7.87(m,2H),7.78–7.65(m,2H ),6.92–6.87(m,1H),6.80–6.71(m,2H),5.11–5.02(m,1H),4.43–4.30(m,2H),4.24–4.12(m,2H),4.08–3.96 (m,1H),3.12–2.97(m,2H),2.97–2.80(m,3H),2.72–2.50(m,2H),2.10–1.95(m,3H).
实施例29：化合物29的制备
Example 29: Preparation of Compound 29
第一步：29b的制备Step 1: Preparation of 29b
将29a(2g，7.63mmol)加入40mL乙腈，依次加入2-溴-2-甲基丙酸甲酯(1.5g，8.29mmol)和碳酸铯(4.9g，15.04mmol)，90℃反应16h。将反应体系冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝17:3)，得29b(2.7g，收率：98％)。Add 29a (2g, 7.63mmol) to 40mL acetonitrile, add 2-bromo-2-methylpropionic acid methyl ester (1.5g, 8.29mmol) and cesium carbonate (4.9g, 15.04mmol) in sequence, and react at 90°C for 16h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 17:3) to obtain 29b (2.7g, yield: 98 %).
1H NMR(400MHz,CDCl3)δ7.70–7.66(m,1H),3.73(s,3H),1.86(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.70–7.66(m,1H),3.73(s,3H),1.86(s,6H).
第二步：29c的制备Step 2: Preparation of 29c
将29b(2.7g，7.46mmol)溶于40mL四氢呋喃中，加入10mL水，冷却至0℃，加入一水合氢氧化锂(1.5g，35.75mmol)，室温反应2h。将反应体系用0.5mol/L盐酸调pH至4，用乙酸乙酯萃取(80mL×3)，有机相用饱和氯化钠水溶液洗涤(80mL×2)，无水硫酸钠干燥，减压浓缩，得粗品(2.1g)。将上述粗品(200mg)加入到50mL单口瓶中，加入15mL二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺(115mg，0.86mmol)，室温反应1h后，依次加入三乙胺(172mg，1.70mmol)和16B(90mg，0.57mmol)，室温反应1h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝91:9)，得29c(190mg，收率：68％)。Dissolve 29b (2.7g, 7.46mmol) in 40mL tetrahydrofuran, add 10mL water, cool to 0°C, add lithium hydroxide monohydrate (1.5g, 35.75mmol), and react at room temperature for 2h. Adjust the pH of the reaction system to 4 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (80 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (80 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain crude product (2.1g). Add the above crude product (200mg) into a 50mL single-neck bottle, add 15mL dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (115mg, 0.86mmol), and after reacting at room temperature for 1 hour, add three Ethylamine (172 mg, 1.70 mmol) and 16B (90 mg, 0.57 mmol) were reacted at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 91:9) to obtain 29c (190 mg, yield: 68%).
LCMS m/z＝489.1[M+1]+ LCMS m/z＝489.1[M+1] +
第三步；化合物29的制备Step 3: Preparation of compound 29
将29c(90mg，0.18mmol)加入10mL DMF，加入粗品中间体1(93mg)和三乙胺(55mg，0.54mmol)、PdCl2(PPh3)2(13mg，0.019mmol)和CuI(7mg，0.037mmol)，置换氮气三次，50℃反应2h。将反应体系冷却至室温，缓慢加入10mL饱和氯化铵水溶液，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝22:78)，得化合物29(52mg，收率：41％)。Add 29c (90 mg, 0.18 mmol) to 10 mL DMF, add crude intermediate 1 (93 mg) and triethylamine (55 mg, 0.54 mmol), PdCl 2 (PPh 3 ) 2 (13 mg, 0.019 mmol) and CuI (7 mg, 0.037 mmol), replaced with nitrogen three times, and reacted at 50°C for 2 hours. Cool the reaction system to room temperature, slowly add 10 mL of saturated aqueous ammonium chloride solution, extract with ethyl acetate (50 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, and reduce pressure. After concentration, the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=22:78) to obtain compound 29 (52 mg, yield: 41%).
1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.36(d,1H),7.96–7.82(m,2H),7.74–7.63(m,1H),7.54–7.46(m,1H),7.42–7.35(m,1H),6.83–6.78(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–3.97(m,2H),3.90–3.75(m,1H),2.98–2.64(m,3H),2.18–2.07(m,1H),1.99(s,6H),1.59–1.46(m,1H),1.06–0.98(m,2H),0.62–0.55(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.89(s,1H),8.36(d,1H),7.96–7.82(m,2H),7.74–7.63(m,1H),7.54–7.46(m,1H ),7.42–7.35(m,1H),6.83–6.78(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–3.97(m ,2H),3.90–3.75(m,1H),2.98–2.64(m,3H),2.18–2.07(m,1H),1.99(s,6H),1.59–1.46(m,1H),1.06–0.98 (m,2H),0.62–0.55(m,2H).
实施例30：化合物30的制备
Example 30: Preparation of Compound 30
化合物30以29b与17B为原料，参考实施例29得到化合物30(60mg)。Compound 30 was prepared by using 29b and 17B as raw materials and referring to Example 29 to obtain compound 30 (60 mg).
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.40(d,1H),7.96(s,1H),7.88–7.82(m,1H),7.68(d,1H),7.61–7.56(m,1H),7.53–7.46(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H),3.88–3.75(m,1H),2.97–2.65(m,3H),2.18–2.07(m,4H),1.97(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.49(s,1H),8.40(d,1H),7.96(s,1H),7.88–7.82(m,1H),7.68(d,1H),7.61– 7.56(m,1H),7.53–7.46(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H), 4.10–4.00(m,2H),3.88–3.75(m,1H),2.97–2.65(m,3H),2.18–2.07(m,4H),1.97(s,6H).
实施例31：化合物31的制备
Example 31: Preparation of Compound 31
第一步：31b的制备Step One: Preparation of 31b
将(甲氧基甲基)三苯基氯化膦(1.65g，4.81mmol)加入到反应瓶中，在氮气保护下加入30mL无水四氢呋喃，冷却至0℃，加入叔丁醇钾(0.57g，5.08mmol)，0℃搅拌0.5h后，加入31a(0.5g，3.21mmol)，室温反应19h。向反应液中加入70mL水，用乙酸乙酯萃取(80mL×3)，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-5:1)，得31b(0.12g，收率：20％)。Add (methoxymethyl)triphenylphosphine chloride (1.65g, 4.81mmol) into the reaction bottle, add 30mL anhydrous tetrahydrofuran under nitrogen protection, cool to 0°C, and add potassium tert-butoxide (0.57g , 5.08mmol), stirred at 0°C for 0.5h, then added 31a (0.5g, 3.21mmol), and reacted at room temperature for 19h. Add 70 mL of water to the reaction solution, extract with ethyl acetate (80 mL )=10:1-5:1) to obtain 31b (0.12g, yield: 20%).
LCMS m/z＝184.1[M+1]+ LCMS m/z＝184.1[M+1] +
第二步：31c的制备Step 2: Preparation of 31c
将31b(0.11g，0.60mmol)溶于3mL THF中，加入3mL 6mol/L盐酸，室温反应2h。向反 应液中加入10mL水，用饱和碳酸氢钠水溶液调pH至7，用20mL乙酸乙酯萃取，分离出有机相，无水硫酸钠干燥，减压浓缩，得到粗品31c(0.11g)。Dissolve 31b (0.11g, 0.60mmol) in 3mL THF, add 3mL 6mol/L hydrochloric acid, and react at room temperature for 2h. reverse Add 10 mL of water to the reaction solution, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, extract with 20 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 31c (0.11g).
化合物31以化合物31c为原料，参考实施例22得到化合物31(5mg)。Compound 31 Compound 31 (5 mg) was obtained by referring to Example 22 using compound 31c as a raw material.
1H NMR(400MHz,CDCl3)δ8.37–8.22(m,2H),7.80–7.42(m,4H),7.22–7.17(m,1H),7.13–7.05(m,1H),6.85–6.77(m,1H),6.64–6.52(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.13–2.67(m,9H),2.59(s,6H),2.30–1.96(m,5H). 1 H NMR (400MHz, CDCl 3 ) δ8.37–8.22(m,2H),7.80–7.42(m,4H),7.22–7.17(m,1H),7.13–7.05(m,1H),6.85–6.77 (m,1H),6.64–6.52(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H) ,3.13–2.67(m,9H),2.59(s,6H),2.30–1.96(m,5H).
LCMS m/z＝682.2[M+1]+ LCMS m/z＝682.2[M+1] +
实施例32：化合物32的制备
Example 32: Preparation of Compound 32
以化合物32b为原料，参考实施例19得到化合物32(60mg)。Using compound 32b as a raw material, compound 32 (60 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.46(d,1H),8.05(s,1H),7.80(s,1H),7.72(s,1H),7.67(d,1H),7.60–7.56(m,1H),7.51–7.45(m,1H),6.83–6.79(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.10–3.97(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.52(q,2H),2.18–2.08(m,1H),1.94(s,6H),1.29(t,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.89(s,1H),8.46(d,1H),8.05(s,1H),7.80(s,1H),7.72(s,1H),7.67(d, 1H),7.60–7.56(m,1H),7.51–7.45(m,1H),6.83–6.79(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.44–4.30( m,2H),4.10–3.97(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.52(q,2H),2.18–2.08(m,1H),1.94( s,6H),1.29(t,3H).
实施例33：化合物33的制备
Example 33: Preparation of Compound 33
以33b为原料，参考实施例19得到化合物33(11mg)。Using 33b as a raw material, compound 33 (11 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.49(d,1H),8.03–7.95(m,1H),7.80(s,1H),7.74(s,1H),7.70–7.59(m,2H),7.56–7.48(m,1H),6.83–6.76(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.28(m,2H),4.12–3.99(m,2H),3.88–3.75(m,1H),3.59(s,2H),2.95–2.65(m,3H),2.39(s,6H),2.18–2.08(m,1H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.87(s,1H),8.49(d,1H),8.03–7.95(m,1H),7.80(s,1H),7.74(s,1H),7.70– 7.59(m,2H),7.56–7.48(m,1H),6.83–6.76(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.28(m,2H), 4.12–3.99(m,2H),3.88–3.75(m,1H),3.59(s,2H),2.95–2.65(m,3H),2.39(s,6H),2.18–2.08(m,1H), 1.94(s,6H).
LCMS m/z＝714.2[M+1]+ LCMS m/z＝714.2[M+1] +
实施例34：化合物34的制备
Example 34: Preparation of Compound 34
以化合物34a+2-溴-2-甲基丙酸甲酯为原料，参考实施例29得到化合物34(70mg)。Using compound 34a + methyl 2-bromo-2-methylpropionate as raw materials, compound 34 (70 mg) was obtained with reference to Example 29.
1H NMR(400MHz,CDCl3)δ8.55–8.37(m,2H),7.92(s,1H),7.72–7.65(m,2H),7.60–7.45 (m,2H),6.84–6.78(m,1H),6.60–6.52(m,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.10–4.00(m,2H),3.90–3.77(m,1H),2.96–2.64(m,3H),2.20–1.95(m,5H),1.86(s,6H),1.09–1.02(m,2H),1.00–0.92(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.55–8.37(m,2H),7.92(s,1H),7.72–7.65(m,2H),7.60–7.45 (m,2H),6.84–6.78(m,1H),6.60–6.52(m,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.10–4.00(m,2H) ,3.90–3.77(m,1H),2.96–2.64(m,3H),2.20–1.95(m,5H),1.86(s,6H),1.09–1.02(m,2H),1.00–0.92(m, 2H).
LCMS m/z＝711.2[M+1]+ LCMS m/z＝711.2[M+1] +
实施例35：化合物35的制备
Example 35: Preparation of Compound 35
以化合物34b+16B为原料，参考实施例29得到化合物35(50mg)。Using compound 34b+16B as raw materials, compound 35 (50 mg) was obtained with reference to Example 29.
1H NMR(400MHz,CDCl3)δ8.86(s,1H),8.36(d,1H),7.97(s,1H),7.72–7.64(m,2H),7.49(dd,1H),7.38–7.32(m,1H),6.84–6.77(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H),3.90–3.75(m,1H),2.97–2.62(m,3H),2.22–1.82(m,8H),1.66–1.46(m,1H),1.06–0.78(m,6H),0.60–0.50(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.86(s,1H),8.36(d,1H),7.97(s,1H),7.72–7.64(m,2H),7.49(dd,1H),7.38– 7.32(m,1H),6.84–6.77(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H), 3.90–3.75(m,1H),2.97–2.62(m,3H),2.22–1.82(m,8H),1.66–1.46(m,1H),1.06–0.78(m,6H),0.60–0.50(m ,2H).
LCMS m/z＝670.3[M+1]+ LCMS m/z＝670.3[M+1] +
实施例36：化合物36的制备
Example 36: Preparation of Compound 36
以化合物36b为原料，参考实施例19得到化合物36(34mg)。Using compound 36b as a raw material, compound 36 (34 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.32(d,1H),8.03(s,1H),7.80(s,1H),7.73(s,1H),7.67(d,1H),7.34–7.20(m,2H),7.02–6.95(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.99–4.88(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H),3.88–3.73(m,1H),2.95–2.64(m,3H),2.18–2.08(m,4H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.55(s,1H),8.32(d,1H),8.03(s,1H),7.80(s,1H),7.73(s,1H),7.67(d, 1H),7.34–7.20(m,2H),7.02–6.95(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.99–4.88(m,1H),4.42–4.30( m,2H),4.10–4.00(m,2H),3.88–3.73(m,1H),2.95–2.64(m,3H),2.18–2.08(m,4H),1.94(s,6H).
实施例37：化合物37的制备
Example 37: Preparation of Compound 37
第一步：37b的制备Step 1: Preparation of 37b
将37a(1.00g，6.32mmol)(合成方法见Bioorganic&Medicinal Chemistry,2012,20,1188-1200)溶于15mL二氯甲烷中，加入三乙胺(1.92g，18.97mmol)，冷却至0℃，滴加MsCl(0.87g，7.59mmol)，室温反应3h。向反应液中加入20mL水，用二氯甲烷萃取(30mL×3)，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-5:1)，得37b(1.1g，收率：74％)。Dissolve 37a (1.00g, 6.32mmol) (for synthesis methods, see Bioorganic & Medicinal Chemistry, 2012, 20, 1188-1200) in 15mL dichloromethane, add triethylamine (1.92g, 18.97mmol), cool to 0°C, and drop Add MsCl (0.87g, 7.59mmol) and react at room temperature for 3 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (30 mL (v/v)=10:1-5:1), 37b (1.1g, yield: 74%) was obtained.
第二步：37c的制备Step 2: Preparation of 37c
将37b(0.7g，2.96mmol)溶于15mL DMF中，加入碳酸铯(2.89g，8.87mmol)和4-碘吡唑(0.86g，4.43mmol)，80℃反应12h。将反应体系冷却至室温，加入30mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，有机相用无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-5:1)，得37c(0.3g，收率：30％)。Dissolve 37b (0.7g, 2.96mmol) in 15mL DMF, add cesium carbonate (2.89g, 8.87mmol) and 4-iodopyrazole (0.86g, 4.43mmol), and react at 80°C for 12h. Cool the reaction system to room temperature, add 30 mL of water, extract with ethyl acetate (20 mL v/v)=10:1-5:1), 37c (0.3g, yield: 30%) was obtained.
第三步：37d的制备Step 3: Preparation of 37d
将37c(0.38g，1.14mmol)溶于3mL THF/H2O(v/v)＝4:1的混合溶剂中，加入一水合氢氧化锂(72mg，1.72mmol)，40℃反应3h。将反应体系冷却至室温，加入10mL水，用1mol/L盐酸调pH至3，用乙酸乙酯萃取(25mL×3)，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，得粗品(0.34g)。将上述粗品(0.34g)溶于10mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.22g，1.65mmol)，室温反应2h后，依次加入三乙胺(0.34g，3.36mmol)和2-氯-4-(三氟甲基)苯胺(0.22g，1.12mmol)，室温反应19h。向反应液中加入15mL二氯甲烷，加入20mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到37d(0.305g，收率：56％)。Dissolve 37c (0.38g, 1.14mmol) in 3mL of a mixed solvent of THF/H 2 O (v/v) = 4:1, add lithium hydroxide monohydrate (72mg, 1.72mmol), and react at 40°C for 3 hours. Cool the reaction system to room temperature, add 10 mL of water, adjust the pH to 3 with 1 mol/L hydrochloric acid, extract with ethyl acetate (25 mL × 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Crude product (0.34g). Dissolve the above crude product (0.34g) in 10mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.22g, 1.65mmol), react at room temperature for 2 hours, then add triethylamine (0.34g) , 3.36mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.22g, 1.12mmol), reacted at room temperature for 19h. Add 15 mL of methylene chloride to the reaction solution, add 20 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1), obtained 37d (0.305g, yield: 56%).
第四步：化合物37的制备Step 4: Preparation of Compound 37
将37d(305mg，0.63mmol)、粗品中间体1(320mg)、TEA(190mg，1.88mmol)、CuI(24mg，0.126mmol)和PdCl2(PPh3)2(88mg，0.125mmol)加入10mL DMF，氮气氛围55℃反应4h。将反应液冷却至室温，加入25mL水，抽滤，滤饼用5mL水洗涤，将滤饼用100mL DCM/MeOH(v/v)＝5:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝10:1-5:1)，得化合物37(51mg，收率：12％)。37d (305 mg, 0.63 mmol), crude intermediate 1 (320 mg), TEA (190 mg, 1.88 mmol), CuI (24 mg, 0.126 mmol) and PdCl 2 (PPh 3 ) 2 (88 mg, 0.125 mmol) were added to 10 mL DMF, React in nitrogen atmosphere at 55°C for 4 hours. Cool the reaction solution to room temperature, add 25 mL of water, filter with suction, wash the filter cake with 5 mL of water, dissolve the filter cake with 100 mL of a mixed solvent of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and reduce Concentrate under pressure, and the crude product is separated and purified by silica gel chromatography column (dichloromethane/methanol (v/v) = 10:1-5:1) to obtain compound 37 (51 mg, yield: 12%).
1H NMR(400MHz,CDCl3)δ8.46(d,1H),8.27(s,1H),8.04(s,1H),7.77–7.40(m,5H),6.83–6.77(m,1H),6.54(dd,1H),4.98–4.89(m,1H),4.40–4.26(m,2H),4.07–3.96(m,2H),3.84–3.70(m,1H),3.28(s,2H),2.98–2.49(m,7H),2.18–1.96(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.46(d,1H),8.27(s,1H),8.04(s,1H),7.77–7.40(m,5H),6.83–6.77(m,1H), 6.54(dd,1H),4.98–4.89(m,1H),4.40–4.26(m,2H),4.07–3.96(m,2H),3.84–3.70(m,1H),3.28(s,2H), 2.98–2.49(m,7H),2.18–1.96(m,3H).
实施例38：化合物38的制备
Example 38: Preparation of Compound 38
第一步：38b的制备Step 1: Preparation of 38b
将38a(1.5g，9.15mmol)加入到100mL单口瓶中，加入30mL DMF，加入3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(2.5g，13.8mmol)和三乙胺(2.7g，26.7mmol)，置换氮气三次，加入PdCl2(PPh3)2(645mg，0.92mmol)和CuI(350mg，1.84mmol)，置换氮气三次，50℃反应2h。将反应体系冷却至室温，缓慢加入200mL饱和氯化铵水溶液，用乙酸乙酯萃取(100mL×3)，有机相用饱和氯化钠水溶液洗涤(150mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝87:13)，得38b(2g，收率：83％)。Add 38a (1.5g, 9.15mmol) into a 100mL single-neck bottle, add 30mL DMF, add 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (2.5g, 13.8mmol) and triethylamine (2.7 g, 26.7 mmol), replace nitrogen three times, add PdCl 2 (PPh 3 ) 2 (645 mg, 0.92 mmol) and CuI (350 mg, 1.84 mmol), replace nitrogen three times, and react at 50°C for 2 hours. Cool the reaction system to room temperature, slowly add 200 mL of saturated aqueous ammonium chloride solution, extract with ethyl acetate (100 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (150 mL × 2), dry over anhydrous sodium sulfate, and reduce pressure. After concentration, the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=87:13) to obtain 38b (2g, yield: 83%).
LCMS m/z＝265.1[M+1]+ LCMS m/z＝265.1[M+1] +
第二步：38c的制备Step 2: Preparation of 38c
将38b(1.0g，3.79mmol)加入到100mL三口瓶中，加入20mL四氢呋喃，置换氮气三次，冷却至-78℃，缓慢加入2mol/L二异丙基氨基锂的四氢呋喃溶液(3.8mL，7.6mmol)，在-78℃下反应20min后，升温至0℃反应1h。将反应体系冷却至-78℃，加入38A(986mg，5.69mmol)(合成方法见WO2014045031)，室温反应16h。向反应体系中加入50mL饱和氯化铵水溶液，用乙酸乙酯萃取(70mL×3)，有机相用饱和氯化钠水溶液洗涤(80mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝78:22)，得38c(0.35g，收率：21％)。Add 38b (1.0g, 3.79mmol) into a 100mL three-necked flask, add 20mL tetrahydrofuran, replace nitrogen three times, cool to -78°C, and slowly add 2mol/L lithium diisopropylamide tetrahydrofuran solution (3.8mL, 7.6mmol) ), after reacting at -78°C for 20 minutes, the temperature was raised to 0°C and reacted for 1 hour. The reaction system was cooled to -78°C, 38A (986 mg, 5.69 mmol) was added (see WO2014045031 for the synthesis method), and the reaction was carried out at room temperature for 16 hours. Add 50 mL saturated aqueous ammonium chloride solution to the reaction system, extract with ethyl acetate (70 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (80 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is Silica gel column separation and purification (petroleum ether: ethyl acetate (v/v) = 78:22) gave 38c (0.35g, yield: 21%).
LCMS m/z＝438.1[M+1]+ LCMS m/z＝438.1[M+1] +
第三步：38d的盐酸盐的制备Step 3: Preparation of 38d hydrochloride
将38c(0.335g，0.77mmol)溶于15mL甲醇中，冷却至0℃，加入0.5mol/L氯化氢的乙酸乙酯溶液(10mL，5mmol)，在0℃下反应1h。将反应体系减压浓缩，得到粗品38d的盐酸盐(210mg)。Dissolve 38c (0.335g, 0.77mmol) in 15mL methanol, cool to 0°C, add 0.5mol/L hydrogen chloride in ethyl acetate solution (10mL, 5mmol), and react at 0°C for 1 hour. The reaction system was concentrated under reduced pressure to obtain the hydrochloride salt of crude product 38d (210 mg).
第四步：38e的制备Step 4: Preparation of 38e
将2-氯-4-(三氟甲基)苯甲酸(67mg，0.3mmol)加入到50mL单口瓶中，加入10mL二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺(58mg，0.43mmol)，室温反应1h后，依次加入三乙胺(88mg，0.87mmol)和上述粗品38d的盐酸盐(110mg)，室温反应1h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝72:28)，得38e(80mg，收率：49％)。Add 2-chloro-4-(trifluoromethyl)benzoic acid (67 mg, 0.3 mmol) into a 50 mL single-neck bottle, add 10 mL dichloromethane, and add 1-chloro-N,N,2-trimethylpropenylamine (58 mg, 0.43 mmol), and after reacting at room temperature for 1 hour, triethylamine (88 mg, 0.87 mmol) and the hydrochloride of the crude product 38d (110 mg) were added in sequence, and reacted at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=72:28) to obtain 38e (80 mg, yield: 49%).
LCMS m/z＝540.1[M+1]+ LCMS m/z＝540.1[M+1] +
第五步；38f的对甲苯磺酸盐的制备Step 5: Preparation of p-toluenesulfonate of 38f
将38e(80mg，0.15mmol)加入到50mL单口瓶中，加入20mL乙腈，加入对甲苯磺酸(103 mg，0.6mmol)，30℃反应2h。将反应体系减压浓缩，得到粗品38f的对甲苯磺酸盐(70mg)。Add 38e (80 mg, 0.15 mmol) into a 50 mL single-neck bottle, add 20 mL acetonitrile, and add p-toluenesulfonic acid (103 mg, 0.6mmol), react at 30°C for 2 hours. The reaction system was concentrated under reduced pressure to obtain crude product 38f p-toluenesulfonate (70 mg).
LCMS m/z＝440.1[M+1]+ LCMS m/z＝440.1[M+1] +
第六步；化合物38的制备Step 6; Preparation of compound 38
将粗品38f的对甲苯磺酸盐(70mg)加入到50mL单口瓶中，加入6mL DMSO和DIPEA(103mg，0.80mmol)，搅拌20min后，加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(66mg，0.24mmol)，80℃反应2h。将反应体系冷却至室温，缓慢加入80mL水，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝28:72)，得化合物38(25mg，收率：15％)。Add crude 38f p-toluenesulfonate (70 mg) into a 50 mL single-neck bottle, add 6 mL DMSO and DIPEA (103 mg, 0.80 mmol), stir for 20 min, and then add 2-(2,6-dioxopiperidine-3 -base)-5-fluoroisoindoline-1,3-dione (66 mg, 0.24 mmol), react at 80°C for 2 hours. The reaction system was cooled to room temperature, 80 mL of water was slowly added, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride aqueous solution (60 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was Silica gel column separation and purification (petroleum ether: ethyl acetate (v/v) = 28:72) gave compound 38 (25 mg, yield: 15%).
1H NMR(400MHz,CDCl3)δ8.15–8.00(m,1H),7.84–7.54(m,5H),7.14–7.02(m,1H),6.88–6.75(m,1H),6.65–6.50(m,1H),4.99–4.87(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.95–3.80(m,1H),2.97–2.65(m,7H),2.31–2.05(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.15–8.00(m,1H),7.84–7.54(m,5H),7.14–7.02(m,1H),6.88–6.75(m,1H),6.65–6.50 (m,1H),4.99–4.87(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.95–3.80(m,1H),2.97–2.65(m,7H) ,2.31–2.05(m,3H).
实施例39：制备化合物39
Example 39: Preparation of Compound 39
第一步：39b的制备Step 1: Preparation of 39b
将2-氯-4-三氟甲基苯甲酸(0.1g，0.45mmol)溶于2mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.09g，0.67mmol)，室温反应2h后，依次加入三乙胺(0.27g，2.67mmol)和39a(合成方法见WO2016116061)(0.1g，0.40mmol)，室温反应12h。向反应液中加入50mL二氯甲烷，加入50mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝20:1-5:1)，得到39b(0.06g，收率：33％)。Dissolve 2-chloro-4-trifluoromethylbenzoic acid (0.1g, 0.45mmol) in 2mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.09g, 0.67mmol), After reacting at room temperature for 2 hours, triethylamine (0.27g, 2.67mmol) and 39a (see WO2016116061 for the synthesis method) (0.1g, 0.40mmol) were added in sequence, and the reaction was carried out at room temperature for 12h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20 :1-5:1), obtained 39b (0.06g, yield: 33%).
LCMS m/z＝455.0[M+1]+ LCMS m/z＝455.0[M+1] +
第二步：化合物39的制备Step 2: Preparation of Compound 39
将39b(0.06g，0.13mmol)、粗品中间体1(0.044g)、TEA(0.079g，0.78mmol)、CuI(5mg，0.026mmol)和双三苯基膦二氯化钯(9mg，0.013mmol)加入5mL DMF，氮气氛围50℃反应0.5h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2)，得化合物39(0.015g，收率：17％)。39b (0.06g, 0.13mmol), crude intermediate 1 (0.044g), TEA (0.079g, 0.78mmol), CuI (5mg, 0.026mmol) and bistriphenylphosphine palladium dichloride (9mg, 0.013mmol) ) Add 5mL DMF and react in a nitrogen atmosphere at 50°C for 0.5h. Cool the reaction solution to room temperature, add 50 mL of water, and suction filtrate. Wash the filter cake with 10 mL of water. Dissolve the filter cake with 20 mL of DCM and dry it over anhydrous sodium sulfate. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/dichloromethane/ Ethyl acetate (v/v)=1:1:2) to obtain compound 39 (0.015g, yield: 17%).
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.77–7.56(m,3H),7.52–7.40(m,1H),6.84–6.70(m,2H),6.58–6.48(m,1H),6.17–5.82(m,1H),5.04–4.80(m,2H),4.54–3.45(m,10H),2.99–2.62(m,3H),2.20–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,1H),7.77–7.56(m,3H),7.52–7.40(m,1H),6.84–6.70(m,2H),6.58–6.48(m ,1H),6.17–5.82(m,1H),5.04–4.80(m,2H),4.54–3.45(m,10H),2.99–2.62(m,3H),2.20–2.06(m,1H).
LCMS m/z＝664.2[M+1]+ LCMS m/z＝664.2[M+1] +
实施例40：化合物40的三氟乙酸盐的制备
Example 40: Preparation of trifluoroacetate salt of compound 40
第一步：40b的制备Step One: Preparation of 40b
将40a(2.2g，9.9mmol)加入到50mL DMF中，加入28B(4.3g，12mmol)和碳酸铯(6.5g，19.95mmol)，85℃反应3h。将反应液冷却至室温，加入100mL乙酸乙酯和200mL纯化水，分离出有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝4:1)，得40b(1.5g，收率：30％)。Add 40a (2.2g, 9.9mmol) to 50mL DMF, add 28B (4.3g, 12mmol) and cesium carbonate (6.5g, 19.95mmol), and react at 85°C for 3 hours. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 200 mL of purified water were added, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v)=4:1), 40b (1.5g, yield: 30%) was obtained.
第二步：40c的制备Step 2: Preparation of 40c
将40b(0.5g，1.0mmol)加入到30mL 1,2-二氯乙烷中，加入吗啉(0.2g，2.3mmol)，加入三乙酰氧基硼氢化钠(0.42g，1.98mmol)，室温反应12h。向反应液中加入20mL二氯甲烷，加入50mL纯化水，分离出有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝3:1)，得40c(0.38g，收率：67％)。Add 40b (0.5g, 1.0mmol) to 30mL 1,2-dichloroethane, add morpholine (0.2g, 2.3mmol), add sodium triacetoxyborohydride (0.42g, 1.98mmol), room temperature Reaction 12h. Add 20 mL of methylene chloride to the reaction solution, add 50 mL of purified water, and separate the organic phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/ v)=3:1), 40c (0.38g, yield: 67%) was obtained.
LCMS m/z＝569.1[M+1]+ LCMS m/z＝569.1[M+1] +
第三步：40d的制备Step 3: Preparation of 40d
将40c(0.38g，0.67mmol)、3-乙炔基氮杂环丁-1-甲酸叔丁酯(0.18g，0.99mmol)、TEA(0.3g，2.96mmol)、CuI(11mg，0.058mmol)和PdCl2(PPh3)2(42mg，0.06mmol)加入5mL DMF，氮气保护下90℃反应3h。将反应液冷却至室温，加入30mL纯化水，过滤，滤饼用30mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝3:1)，得40d(0.32g，收率：77％)。40c (0.38g, 0.67mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18g, 0.99mmol), TEA (0.3g, 2.96mmol), CuI (11mg, 0.058mmol) and PdCl 2 (PPh 3 ) 2 (42 mg, 0.06 mmol) was added to 5 mL DMF, and the reaction was carried out at 90°C for 3 hours under nitrogen protection. Cool the reaction solution to room temperature, add 30 mL of purified water, filter, dissolve the filter cake with 30 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/ v)=3:1), 40d (0.32g, yield: 77%) was obtained.
LCMS m/z＝622.3[M+1]+LCMS m/z＝622.3[M+1]+
以化合物40d为原料，参考实施例23制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物40的三氟乙酸盐(10mg)。Using compound 40d as raw material, refer to the preparation method of Example 23, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 40 (10 mg).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.21(s,1H),8.52(s,1H),7.98–7.87(m,2H),7.80–7.65(m,2H),6.92–6.86(m,1H),6.73(dd,1H),5.12–5.01(m,1H),4.48–4.28(m,4H),4.15–3.02(m,11H),3.02–2.70(m,5H),2.67–2.46(m,2H),2.08–1.92(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),9.21(s,1H),8.52(s,1H),7.98–7.87(m,2H),7.80–7.65(m,2H ),6.92–6.86(m,1H),6.73(dd,1H),5.12–5.01(m,1H),4.48–4.28(m,4H),4.15–3.02(m,11H),3.02–2.70(m ,5H),2.67–2.46(m,2H),2.08–1.92(m,3H).
LCMS m/z＝778.2[M+1]+ LCMS m/z＝778.2[M+1] +
实施例41：化合物41的三氟乙酸盐的制备
Example 41: Preparation of trifluoroacetate salt of compound 41
第一步：41a的制备Step One: Preparation of 41a
将40b(0.5g，1.0mmol)加入到30mL二氯甲烷中，加入DAST(0.48g，2.98mmol)，室温反应3h。向反应体系中加入2mL甲醇，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝4:1)，得41a(0.31g，收率：60％)。Add 40b (0.5g, 1.0mmol) to 30mL dichloromethane, add DAST (0.48g, 2.98mmol), and react at room temperature for 3h. 2 mL of methanol was added to the reaction system, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 4:1) to obtain 41a (0.31 g, yield: 60%).
第二步：41b的制备Step 2: Preparation of 41b
将41a(0.38g，0.73mmol)、3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(0.18g，0.99mmol)、TEA(0.3g，2.96mmol)、CuI(11mg，0.058mmol)和PdCl2(PPh3)2(42mg，0.06mmol)5mL DMF，氮气氛围下95℃反应3h。将反应液冷却至室温，加入30mL纯化水，过滤，滤饼用30mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝4:1)，得41b(0.32g，收率：77％)。41a (0.38g, 0.73mmol), 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (0.18g, 0.99mmol), TEA (0.3g, 2.96mmol), CuI (11mg, 0.058mmol) and PdCl 2 (PPh 3 ) 2 (42 mg, 0.06 mmol) 5 mL DMF, react at 95°C for 3 hours under nitrogen atmosphere. Cool the reaction solution to room temperature, add 30 mL of purified water, filter, dissolve the filter cake with 30 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/ v)=4:1), 41b (0.32g, yield: 77%) was obtained.
化合物41的三氟乙酸盐以化合物41b为原料，参考实施例23制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物41的三氟乙酸盐(50mg)。The trifluoroacetic acid salt of compound 41 was prepared using compound 41b as raw material, referring to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and lyophilized to obtain the trifluoroacetic acid salt of compound 41. Salt (50mg).
1H NMR(400MHz,CDCl3)δ8.60–8.50(m,2H),8.07–7.98(m,1H),7.73(s,1H),7.67(d,1H),7.62–7.56(m,1H),7.55–7.48(m,1H),6.92–6.60(m,2H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.90–3.76(m,1H),3.15–3.02(m 2H),2.95–2.66(m,5H),2.30–2.02(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.60–8.50(m,2H),8.07–7.98(m,1H),7.73(s,1H),7.67(d,1H),7.62–7.56(m,1H ),7.55–7.48(m,1H),6.92–6.60(m,2H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–4.00(m ,2H),3.90–3.76(m,1H),3.15–3.02(m 2H),2.95–2.66(m,5H),2.30–2.02(m,3H).
LCMS m/z＝727.1[M-1]- LCMS m/z＝727.1[M-1] -
实施例42：化合物42的三氟乙酸盐的制备
Example 42: Preparation of trifluoroacetate salt of compound 42
第一步：42a的制备Step 1: Preparation of 42a
将40b(0.5g，1.0mmol)加入到30mL 1,2-二氯乙烷中，加入二甲胺(0.2g，4.44mmol)，加入三乙酰氧基硼氢化钠(0.42g，1.98mmol)，室温反应12h。向反应液中加入20mL二氯甲烷，加入50mL纯化水，分离出有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:1)，得42a(0.27g，收率：51％)。Add 40b (0.5g, 1.0mmol) to 30mL 1,2-dichloroethane, add dimethylamine (0.2g, 4.44mmol), add sodium triacetoxyborohydride (0.42g, 1.98mmol), React at room temperature for 12 hours. Add 20 mL of methylene chloride to the reaction solution, add 50 mL of purified water, and separate the organic phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/ v)=1:1), 42a (0.27g, yield: 51%) was obtained.
LCMS m/z＝527.1[M+1]+ LCMS m/z＝527.1[M+1] +
第二步：42b的制备Step 2: Preparation of 42b
将42a(0.27g，0.51mmol)、3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(0.18g，0.99mmol)、TEA(0.3 g，2.96mmol)、CuI(11mg，0.058mmol)和PdCl2(PPh3)2(42mg，0.06mmol)加入5mL DMF，氮气氛围下95℃反应3h。将反应液冷却至室温，加入30mL纯化水，过滤，滤饼用30mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝1:1)，得42b(0.25g，收率：85％)。42a (0.27g, 0.51mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18g, 0.99mmol), TEA (0.3 g, 2.96mmol), CuI (11mg, 0.058mmol) and PdCl 2 (PPh 3 ) 2 (42mg, 0.06mmol) were added to 5mL DMF, and the reaction was carried out at 95°C for 3h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 30 mL of purified water, filter, dissolve the filter cake with 30 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/ v)=1:1), 42b (0.25g, yield: 85%) was obtained.
化合物42的三氟乙酸盐以化合物42b为原料，参考实施例23制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物42的三氟乙酸盐(6mg)。The trifluoroacetic acid salt of compound 42 was prepared using compound 42b as the raw material, referring to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetic acid salt of compound 42. Salt (6mg).
1H NMR(400MHz,DMSO-d6)δ11.06(br.s,1H),9.29(s,1H),8.59(s,1H),7.98–7.90(m,1H),7.89–7.81(m,1H),7.78–7.65(m,2H),6.92–6.84(m,1H),6.73(dd,1H),5.14–5.00(m,1H),4.57(s,2H),4.47–4.35(m,2H),4.13–4.02(m,2H),4.01–3.89(m,1H),3.10(s,6H),3.01–2.72(m,5H),2.71–2.50(m,2H),2.08–1.93(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(br.s,1H),9.29(s,1H),8.59(s,1H),7.98–7.90(m,1H),7.89–7.81(m ,1H),7.78–7.65(m,2H),6.92–6.84(m,1H),6.73(dd,1H),5.14–5.00(m,1H),4.57(s,2H),4.47–4.35(m ,2H),4.13–4.02(m,2H),4.01–3.89(m,1H),3.10(s,6H),3.01–2.72(m,5H),2.71–2.50(m,2H),2.08–1.93 (m,3H).
实施例43：化合物43的制备
Example 43: Preparation of Compound 43
第一步：化合物43b的制备Step One: Preparation of Compound 43b
将43a(0.19g，0.73mmol)(合成方法见Bioorganic&Medicinal Chemistry Letters,2021,33,127749)溶于2mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺(0.19g，1.42mmol)，室温反应2h后，依次加入三乙胺(0.58g，5.73mmol)和16B(0.25g，1.58mmol)，室温反应12h。向反应液中加入50mL二氯甲烷，加入50mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝20:1-5:1)，得到43b(0.2g，收率：69％)。Dissolve 43a (0.19g, 0.73mmol) (for synthesis methods, see Bioorganic & Medicinal Chemistry Letters, 2021, 33, 127749) in 2mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.19g, 1.42 mmol), reacted at room temperature for 2 hours, then added triethylamine (0.58g, 5.73mmol) and 16B (0.25g, 1.58mmol) in sequence, and reacted at room temperature for 12h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20 :1-5:1) to obtain 43b (0.2g, yield: 69%).
第二步：化合物43的制备Step 2: Preparation of compound 43
将43b(0.092g，0.23mmol)、粗品中间体1(0.078g)、TEA(0.14g，1.38mmol)、CuI(8.8mg，0.046mmol)和PdCl2(PPh3)2(16mg，0.023mmol)加入2mL DMF，氮气氛围55℃反应1h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2)，得化合物43(0.005g，收率：3％)。43b (0.092g, 0.23mmol), crude intermediate 1 (0.078g), TEA (0.14g, 1.38mmol), CuI (8.8mg, 0.046mmol) and PdCl 2 (PPh 3 ) 2 (16mg, 0.023mmol) Add 2 mL DMF and react at 55°C for 1 hour in a nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 20 mL of DCM and dried over anhydrous sodium sulfate. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/dichloromethane/ Ethyl acetate (v/v)=1:1:2) to obtain compound 43 (0.005g, yield: 3%).
1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.52(d,1H),7.97(s,1H),7.72–7.62(m,1H),7.60–7.51(m,1H),7.51–7.42(m,1H),7.39–7.32(m,2H),6.94–6.87(m,2H),6.84–6.77(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.43–4.32(m,2H),4.13–4.02(m,2H),3.89–3.77(m,1H),2.96–2.64(m,3H),2.19–2.08(m,1H),1.70–1.48(m,7H),0.92–0.78(m,2H),0.58–0.47(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.44(s,1H),8.52(d,1H),7.97(s,1H),7.72–7.62(m,1H),7.60–7.51(m,1H), 7.51–7.42(m,1H),7.39–7.32(m,2H),6.94–6.87(m,2H),6.84–6.77(m,1H),6.56(dd,1H),4.99–4.88(m,1H ),4.43–4.32(m,2H),4.13–4.02(m,2H),3.89–3.77(m,1H),2.96–2.64(m,3H),2.19–2.08(m,1H),1.70–1.48 (m,7H),0.92–0.78(m,2H),0.58–0.47(m,2H).
LCMS m/z＝656.3[M+1]+ LCMS m/z＝656.3[M+1] +
实施例44：化合物44的制备
Example 44: Preparation of Compound 44
第一步：44b的制备Step One: Preparation of 44b
将44a(0.90g,3.63mmol)和1-氯-N,N,2-三甲基丙烯胺(0.73g,5.46mmol)加入二氯甲烷(10mL)，室温搅拌1h后，加入三乙胺(1.51mL)与2-氯-4-(三氟甲基)苯胺(0.85g,4.35mmol)，室温反应16h。将反应液减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20)，得到44b(0.50g,产率：32％)。44a (0.90g, 3.63mmol) and 1-chloro-N,N,2-trimethylpropenylamine (0.73g, 5.46mmol) were added to dichloromethane (10mL). After stirring at room temperature for 1h, triethylamine ( 1.51mL) and 2-chloro-4-(trifluoromethyl)aniline (0.85g, 4.35mmol) at room temperature for 16h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 44b (0.50 g, yield: 32%).
LCMS m/z＝426.0[M+1]+ LCMS m/z＝426.0[M+1] +
第二步：化合物44的制备Step 2: Preparation of Compound 44
将44b(0.17g,0.4mmol)、粗品中间体1(0.20g)、PdCl2(PPh3)2(27mg,0.038mmol)、CuI(15mg,0.079mmol)和DIPEA(0.15g,1.16mmol)加入DMF(5mL)，氮气氛围60℃反应5h。将反应体系冷却至室温，加入到水(20mL)中，用乙酸乙酯/甲醇(v/v)＝5:1的混合溶剂萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:2)，得到的粗品再用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物44(13mg,收率：5％)。44b (0.17g, 0.4mmol), crude intermediate 1 (0.20g), PdCl 2 (PPh 3 ) 2 (27mg, 0.038mmol), CuI (15mg, 0.079mmol) and DIPEA (0.15g, 1.16mmol) were added DMF (5mL), reacted at 60°C for 5h in a nitrogen atmosphere. The reaction system was cooled to room temperature, added to water (20 mL), and extracted with a mixed solvent of ethyl acetate/methanol (v/v) = 5:1 (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and reduced to Concentrate under pressure, and the crude product is separated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) = 1:2). The obtained crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to obtain compound 44 (13 mg, yield: 5%).
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.36(s,1H),8.09(s,1H),8.02–7.93(m,2H),7.92–7.85(m,1H),7.82–7.74(m,1H),7.74–7.65(m,2H),7.62–7.53(m,1H),6.93–6.85(m,1H),6.74(dd,1H),5.12–5.01(m,1H),4.50–4.36(m,2H),4.17–3.90(m,3H),3.00–2.80(m,1H),2.67–2.50(m,2H),2.10–1.92(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.05(s,1H),10.36(s,1H),8.09(s,1H),8.02–7.93(m,2H),7.92–7.85(m,1H) ),7.82–7.74(m,1H),7.74–7.65(m,2H),7.62–7.53(m,1H),6.93–6.85(m,1H),6.74(dd,1H),5.12–5.01(m ,1H),4.50–4.36(m,2H),4.17–3.90(m,3H),3.00–2.80(m,1H),2.67–2.50(m,2H),2.10–1.92(m,1H).
LCMS m/z＝635.0[M+1]+ LCMS m/z＝635.0[M+1] +
实施例45：化合物45的制备
Example 45: Preparation of Compound 45
以化合物45a为原料，参考实施例43得到化合物45(15mg)。Using compound 45a as a raw material, compound 45 (15 mg) was obtained with reference to Example 43.
1H NMR(400MHz,CDCl3)δ8.45(d,1H),7.94(s,1H),7.74(s,1H),7.68(d,1H),7.53–7.40(m,5H),7.36–7.32(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.45–4.32(m,2H),4.17–4.07(m,2H),3.94–3.80(m,1H),2.96–2.66(m,3H),2.18–2.08(m,1H),1.69(s,6H),1.20–1.10(m,1H),0.56–0.47(m,2H),0.36–0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.45(d,1H),7.94(s,1H),7.74(s,1H),7.68(d,1H),7.53–7.40(m,5H),7.36– 7.32(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.45–4.32(m,2H),4.17–4.07(m,2H), 3.94–3.80(m,1H),2.96–2.66(m,3H),2.18–2.08(m,1H),1.69(s,6H),1.20–1.10(m,1H),0.56–0.47(m,2H ),0.36–0.28(m,2H).
LCMS m/z＝640.3[M+1]+ LCMS m/z＝640.3[M+1] +
实施例46：化合物46的制备
Example 46: Preparation of Compound 46
以化合物46a+2-氯-4-(三氟甲基)苯胺为原料，参考实施例43得到化合物46(12mg)。 Using compound 46a + 2-chloro-4-(trifluoromethyl)aniline as raw materials, compound 46 (12 mg) was obtained with reference to Example 43.
1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.93(s,1H),7.72–7.64(m,1H),7.57(s,1H),7.54–7.46(m,4H),7.38–7.30(m,2H),6.84–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.44–4.32(m,2H),4.18–4.07(m,2H),3.93–3.80(m,1H),3.00–2.66(m,5H),2.64–2.51(m,2H),2.30–2.07(m,2H),2.03–1.90(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.56(d,1H),7.93(s,1H),7.72–7.64(m,1H),7.57(s,1H),7.54–7.46(m,4H), 7.38–7.30(m,2H),6.84–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.44–4.32(m,2H),4.18–4.07(m,2H ),3.93–3.80(m,1H),3.00–2.66(m,5H),2.64–2.51(m,2H),2.30–2.07(m,2H),2.03–1.90(m,1H).
实施例47：化合物47的三氟乙酸盐的制备
Example 47: Preparation of trifluoroacetate salt of compound 47
第一步：47b的制备Step One: Preparation of 47b
将47a(0.7g，2.27mmol)(合成方法见WO2012074951)溶于10mL甲醇中，加入一水合氢氧化锂(0.29g，6.91mmol)的水溶液(5mL)，室温反应2h。向反应体系中加入50mL水，用1mol/L盐酸调pH至2，用乙酸乙酯萃取(50mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得到粗品(0.7g)。将上述粗品(0.2g)溶于2mL DCM中，加入16B(0.11g，0.70mmol)、TCFH(0.38g，1.36mmol)和N-甲基咪唑(0.28g，3.41mmol)，室温反应12h。向反应液中加入50mL二氯甲烷，加入50mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝20:1-5:1)，得到47b(0.2g，收率：66％)。Dissolve 47a (0.7g, 2.27mmol) (see WO2012074951 for synthesis method) in 10mL methanol, add an aqueous solution of lithium hydroxide monohydrate (0.29g, 6.91mmol) (5mL), and react at room temperature for 2h. Add 50 mL of water to the reaction system, adjust the pH to 2 with 1 mol/L hydrochloric acid, extract with ethyl acetate (50 mL × 3), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (0.7 g). Dissolve the above crude product (0.2g) in 2mL DCM, add 16B (0.11g, 0.70mmol), TCFH (0.38g, 1.36mmol) and N-methylimidazole (0.28g, 3.41mmol), and react at room temperature for 12h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20 :1-5:1), obtained 47b (0.2g, yield: 66%).
第二步：化合物47的三氟乙酸盐的制备Step 2: Preparation of the trifluoroacetate salt of compound 47
将47b(0.1g，0.23mmol)、粗品中间体1(0.12g)、TEA(0.14g，1.38mmol)、CuI(8.8mg，0.046mmol)和PdCl2(PPh3)2(16mg，0.023mmol)加入2mL DMF，氮气氛围下55℃反应1h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，减压浓缩后粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得到化合物47的三氟乙酸盐(0.05g)。47b (0.1g, 0.23mmol), crude intermediate 1 (0.12g), TEA (0.14g, 1.38mmol), CuI (8.8mg, 0.046mmol) and PdCl 2 (PPh 3 ) 2 (16mg, 0.023mmol) Add 2 mL DMF and react at 55°C for 1 hour under nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, suction filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 20 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure and pass the crude product through Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 47 (0.05g).
1H NMR(400MHz,CDCl3)δ8.44–8.32(m,2H),8.12(s,1H),7.67(d,1H),7.58–7.50(m,3H),7.48–7.43(m,1H),6.83–6.75(m,1H),6.54(dd,1H),4.98–4.89(m,1H),4.41–4.27(m,4H),4.08–3.98(m,2H),3.83–3.71(m,1H),2.97–2.64(m,3H),2.19–2.08(m,1H),1.69–1.52(m,1H),1.40(s,6H),1.06–0.96(m,2H),0.67–0.58(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.44–8.32(m,2H),8.12(s,1H),7.67(d,1H),7.58–7.50(m,3H),7.48–7.43(m,1H ),6.83–6.75(m,1H),6.54(dd,1H),4.98–4.89(m,1H),4.41–4.27(m,4H),4.08–3.98(m,2H),3.83–3.71(m ,1H),2.97–2.64(m,3H),2.19–2.08(m,1H),1.69–1.52(m,1H),1.40(s,6H),1.06–0.96(m,2H),0.67–0.58 (m,2H).
LCMS m/z＝644.8[M+1]+ LCMS m/z＝644.8[M+1] +
实施例48：化合物48的制备
Example 48: Preparation of Compound 48
第一步：48b-A和48b-B的制备Step One: Preparation of 48b-A and 48b-B
将28B(0.4g,1.12mmol)、28a(0.22g,1.13mmol)、碳酸铯(0.73g,2.24mmol)加入乙腈(10mL)，50℃反应4h。将反应体系冷却至室温，过滤，将滤液减压除去溶剂，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20)，分别得到48b-A(0.14g,产率：26％)和48b-B(65mg,产率：12％)。28B (0.4g, 1.12mmol), 28a (0.22g, 1.13mmol), and cesium carbonate (0.73g, 2.24mmol) were added to acetonitrile (10mL), and the reaction was carried out at 50°C for 4 hours. The reaction system was cooled to room temperature, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 48b-A (0.14g, Yield: 26%) and 48b-B (65 mg, yield: 12%).
48b-A的核磁数据：NMR data of 48b-A:
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.57(d,1H),7.64–7.56(m,1H),7.55–7.46(m,1H),7.46–7.40(m,1H),6.62–6.56(m,1H),3.15–3.00(m,2H),2.84–2.72(m,2H),2.32–2.01(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.87(s,1H),8.57(d,1H),7.64–7.56(m,1H),7.55–7.46(m,1H),7.46–7.40(m,1H ),6.62–6.56(m,1H),3.15–3.00(m,2H),2.84–2.72(m,2H),2.32–2.01(m,2H).
48b-B的核磁数据：NMR data of 48b-B:
1H NMR(400MHz,CDCl3)δ8.64–8.55(m,1H),7.72–7.64(m,1H),7.60–7.56(m,3H),6.64–6.58(m,1H),3.20–2.99(m,4H),2.33–2.16(m,1H),2.09–1.93(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.64–8.55(m,1H),7.72–7.64(m,1H),7.60–7.56(m,3H),6.64–6.58(m,1H),3.20–2.99 (m,4H),2.33–2.16(m,1H),2.09–1.93(m,1H).
第二步：化合物48的制备Step 2: Preparation of Compound 48
将48b-A(0.14g,0.30mmol)、中间体1(0.15g)、PdCl2(PPh3)2(21mg,0.030mmol)、CuI(11mg,0.060mmol)和DIPEA(0.12g,0.93mmol)加入DMF(5mL)，氮气氛围60℃反应3h。将反应体系冷却至室温，加入到水(20mL)中，用乙酸乙酯/甲醇的混合溶剂(v/v)＝5:1萃取(20mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:2)，得到的粗品再用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物48(101mg,收率：50％)。48b-A (0.14g, 0.30mmol), intermediate 1 (0.15g), PdCl 2 (PPh 3 ) 2 (21mg, 0.030mmol), CuI (11mg, 0.060mmol) and DIPEA (0.12g, 0.93mmol) DMF (5 mL) was added, and the reaction was carried out at 60°C for 3 hours in a nitrogen atmosphere. Cool the reaction system to room temperature, add it to water (20 mL), extract with a mixed solvent of ethyl acetate/methanol (v/v) = 5:1 (20 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the crude product is separated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) = 1:2). The obtained crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) )=1:1) to obtain compound 48 (101 mg, yield: 50%).
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.55(dd,1H),7.95(s,1H),7.68(d,1H),7.61–7.54(m,2H),7.54–7.47(m,1H),6.86–6.80(m,1H),6.57(dd,1H),6.54–6.50(m,1H),4.99–4.89(m,1H),4.45–4.34(m,2H),4.19–4.10(m,2H),3.94–3.81(m,1H),3.15–3.01(m,2H),2.95–2.65(m,5H),2.34–2.02(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.77(s,1H),8.55(dd,1H),7.95(s,1H),7.68(d,1H),7.61–7.54(m,2H),7.54– 7.47(m,1H),6.86–6.80(m,1H),6.57(dd,1H),6.54–6.50(m,1H),4.99–4.89(m,1H),4.45–4.34(m,2H), 4.19–4.10(m,2H),3.94–3.81(m,1H),3.15–3.01(m,2H),2.95–2.65(m,5H),2.34–2.02(m,3H).
LCMS m/z＝679.2[M+1]+ LCMS m/z＝679.2[M+1] +
实施例49：化合物49的制备
Example 49: Preparation of Compound 49
以化合物48b-B为原料，参考实施例48得到化合物49(12mg)。Using compound 48b-B as a raw material, compound 49 (12 mg) was obtained with reference to Example 48.
1H NMR(400MHz,CDCl3)δ8.54(d,1H),7.91(s,1H),7.73(s,1H),7.71–7.64(m,2H),7.57– 7.53(m,1H),7.48–7.42(m,1H),6.82–6.76(m,1H),6.58–6.51(m,2H),4.99–4.89(m,1H),4.37–4.26(m,2H),4.08–3.97(m,2H),3.84–3.72(m,1H),3.12–2.96(m,4H),2.95–2.66(m,3H),2.32–1.99(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.54(d,1H),7.91(s,1H),7.73(s,1H),7.71–7.64(m,2H),7.57– 7.53(m,1H),7.48–7.42(m,1H),6.82–6.76(m,1H),6.58–6.51(m,2H),4.99–4.89(m,1H),4.37–4.26(m,2H ),4.08–3.97(m,2H),3.84–3.72(m,1H),3.12–2.96(m,4H),2.95–2.66(m,3H),2.32–1.99(m,3H).
LCMS m/z＝679.1[M+1]+ LCMS m/z＝679.1[M+1] +
实施例50：化合物50的制备
Example 50: Preparation of Compound 50
第一步：50b的制备Step One: Preparation of 50b
将50a(合成方法见WO2014086316)(45mg,0.13mmol)、2c(61mg,0.13mmol)、Pd(dppf)Cl2·CH2Cl2(CAS:95464-05-4)(11mg,0.0136mmol)、碳酸钾(54mg,0.39mmol)加入1,4-二氧六环与水的混合溶液(6mL,v/v＝5:1)中，氮气氛围90℃反应16h，将反应液冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝4:1)，得到50b(42mg,产率：56％)。50a (see WO2014086316 for synthesis method) (45mg, 0.13mmol), 2c (61mg, 0.13mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (CAS: 95464-05-4) (11mg, 0.0136mmol), Potassium carbonate (54 mg, 0.39 mmol) was added to a mixed solution of 1,4-dioxane and water (6 mL, v/v = 5:1), and the reaction was carried out at 90°C for 16 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. , the filtrate was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 50b (42 mg, yield: 56%).
LCMS m/z＝575.1[M+1]+ LCMS m/z＝575.1[M+1] +
以化合物50b为原料，参考实施例23得到化合物50(22mg)。Using compound 50b as a raw material, compound 50 (22 mg) was obtained with reference to Example 23.
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.58(d,1H),8.01(s,2H),7.83(s,1H),7.69(d,1H),7.59–7.47(m,4H),7.40–7.34(m,2H),6.89–6.83(m,1H),6.61(dd,1H),4.98–4.90(m,1H),4.54–4.42(m,2H),4.14–3.98(m,3H),3.19–3.05(m,2H),2.96–2.65(m,5H),2.43–1.95(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.77(s,1H),8.58(d,1H),8.01(s,2H),7.83(s,1H),7.69(d,1H),7.59–7.47( m,4H),7.40–7.34(m,2H),6.89–6.83(m,1H),6.61(dd,1H),4.98–4.90(m,1H),4.54–4.42(m,2H),4.14– 3.98(m,3H),3.19–3.05(m,2H),2.96–2.65(m,5H),2.43–1.95(m,3H).
实施例51：化合物51的制备
Example 51: Preparation of Compound 51
第一步：51b的制备Step One: Preparation of 51b
将51a(2.0g，8.51mmol)溶于25mL二氯甲烷中，加入1-氯-N,N,2-三甲基丙烯胺(1.71g，12.80mmol)，室温反应2h。将反应体系缓慢滴加到10mL浓氨水中，室温反应30min。向反应体系中加入50mL饱和碳酸氢钠水溶液，用50mL二氯甲烷萃取，有机相用30mL水洗涤，无水硫酸钠干燥，减压浓缩，得粗品51b(1.5g)。Dissolve 51a (2.0g, 8.51mmol) in 25mL dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (1.71g, 12.80mmol), and react at room temperature for 2h. The reaction system was slowly added dropwise to 10 mL of concentrated ammonia water, and the reaction was carried out at room temperature for 30 min. Add 50 mL of saturated aqueous sodium bicarbonate solution to the reaction system, extract with 50 mL of methylene chloride, wash the organic phase with 30 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 51b (1.5 g).
第二步：51c的制备Step 2: Preparation of 51c
将上述粗品51b(1.5g)溶解在20mL四氢呋喃中，加入劳森试剂(CAS:19172-47-5)(2.59g，6.40mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙 酯(v/v)＝4:1)，得51c(1.5g，收率：94％)。Dissolve the above crude product 51b (1.5g) in 20 mL tetrahydrofuran, add Lawson's reagent (CAS: 19172-47-5) (2.59g, 6.40mmol), and react at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate). Ester (v/v)=4:1), 51c (1.5g, yield: 94%) was obtained.
第三步：51d的制备Step 3: Preparation of 51d
将51c(250mg，1.00mmol)溶于5mL 1,4-二氧六环中，加入1-溴-3-甲基丁-2-酮(200mg,1.21mmol)，置于封管中100℃反应16h。将反应体系冷却至室温，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得51d(0.18g，收率：57％)。Dissolve 51c (250mg, 1.00mmol) in 5mL of 1,4-dioxane, add 1-bromo-3-methylbutan-2-one (200mg, 1.21mmol), place in a sealed tube and react at 100°C 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 51d (0.18g, yield: 57%).
LCMS m/z＝317.0[M+1]+.LCMS m/z＝317.0[M+1] + .
第四步：51e的制备Step 4: Preparation of 51e
将化合物51d(180mg，0.57mmol)溶于10mL甲醇中，加入0.1g 10％钯碳，置换氢气三次，置于氢气球氛围下室温反应16h。将反应体系过滤，将滤液减压浓缩，得粗品51e(0.14g)。Compound 51d (180 mg, 0.57 mmol) was dissolved in 10 mL of methanol, 0.1 g of 10% palladium on carbon was added, hydrogen was replaced three times, and the mixture was placed under a hydrogen balloon atmosphere at room temperature for 16 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 51e (0.14g).
LCMS m/z＝287.3[M+1]+ LCMS m/z＝287.3[M+1] +
以化合物51e为原料，参考实施例18得到化合物51(0.08g)。Using compound 51e as a raw material, compound 51 (0.08g) was obtained with reference to Example 18.
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.28–8.22(m,1H),8.20–8.15(m,1H),8.07–8.00(m,1H),7.97(s,1H),7.81–7.75(m,2H),7.67(d,1H),6.92–6.87(m,1H),6.84–6.79(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.41–4.31(m,2H),4.14–4.02(m,2H),3.88–3.76(m,1H),3.22–3.08(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.95(s,6H),1.35(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.87(s,1H),8.28–8.22(m,1H),8.20–8.15(m,1H),8.07–8.00(m,1H),7.97(s,1H ),7.81–7.75(m,2H),7.67(d,1H),6.92–6.87(m,1H),6.84–6.79(m,1H),6.56(dd,1H),4.98–4.88(m,1H ),4.41–4.31(m,2H),4.14–4.02(m,2H),3.88–3.76(m,1H),3.22–3.08(m,1H),2.95–2.65(m,3H),2.18–2.08 (m,1H),1.95(s,6H),1.35(d,6H).
实施例52：化合物52的制备
Example 52: Preparation of Compound 52
第一步：52d的制备Step One: Preparation of 52d
将叔丁醇钾(2.0g，17.82mmol)与CuI(1.13g，5.93mmol)溶于30mL超干DMF中，氮气保护下冷却至0℃，加入(二氟甲基)三甲基硅烷(1.48g，11.92mmol)，置换氮气三次，0℃搅拌15min后，加入菲-9,10-二酮(1.48g，7.11mmol)，缓慢滴加52c(1.098g,5.93mmol)的DMF溶液(10mL)，0℃反应1h，室温反应16h。向反应体系里加入80mL饱和氯化铵水溶液，垫硅藻土过滤，将滤液用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝8:1),得52d(0.35g，收率：25％)。Dissolve potassium tert-butoxide (2.0g, 17.82mmol) and CuI (1.13g, 5.93mmol) in 30mL of ultra-dry DMF, cool to 0°C under nitrogen protection, and add (difluoromethyl)trimethylsilane (1.48 g, 11.92mmol), replace nitrogen three times, stir at 0°C for 15 minutes, add phenanthrene-9,10-dione (1.48g, 7.11mmol), and slowly add 52c (1.098g, 5.93mmol) DMF solution (10mL) dropwise , react at 0℃ for 1h, and at room temperature for 16h. Add 80 mL of saturated aqueous ammonium chloride solution to the reaction system, filter through diatomaceous earth, extract the filtrate with 100 mL of ethyl acetate, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated on a silica gel chromatography column. Purify (petroleum ether/ethyl acetate (v/v)=8:1) to obtain 52d (0.35g, yield: 25%).
以化合物52d为原料，参考实施例23得到化合物52(30mg)。Using compound 52d as a raw material, compound 52 (30 mg) was obtained with reference to Example 23.
1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.53(d,1H),8.03(s,1H),7.82–7.76(m,2H),7.74–7.59(m,3H),6.85–6.77(m,1H),6.70–6.35(m,2H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.74(m,1H),2.97–2.64(m,3H),2.19–2.05(m,1H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.31(s,1H),8.53(d,1H),8.03(s,1H),7.82–7.76(m,2H),7.74–7.59(m,3H), 6.85–6.77(m,1H),6.70–6.35(m,2H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.74(m ,1H),2.97–2.64(m,3H),2.19–2.05(m,1H),1.94(s,6H).
LCMS m/z＝707.2[M+1]+.LCMS m/z＝707.2[M+1] + .
实施例53：化合物53的制备
Example 53: Preparation of Compound 53
第一步：53B的制备Step One: Preparation of 53B
将53A(1.0g，5.99mmol)加入到100mL单口瓶中，依次加入干燥二氯甲烷(20mL)、16B(952mg，6.02mmol)和TCFH(2.5g，8.91mmol)，缓慢滴加N-甲基咪唑(2.46g，29.96mmol)，室温反应3h。将反应体系过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝93:7)，得53B(1.5g，收率：82％)。Add 53A (1.0g, 5.99mmol) into a 100mL single-mouth bottle, add dry dichloromethane (20mL), 16B (952mg, 6.02mmol) and TCFH (2.5g, 8.91mmol) in sequence, and slowly add N-methyl Imidazole (2.46g, 29.96mmol), react at room temperature for 3h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 93:7) to obtain 53B (1.5 g, yield: 82%).
LCMS m/z＝307.1[M+1]+ LCMS m/z＝307.1[M+1] +
第二步：53b的制备Step 2: Preparation of 53b
将3-乙炔基氮杂环丁烷盐酸盐(540mg，4.59mmol)和碳酸钾(1.3g，9.41mmol)加入到100mL单口瓶中，加入20mL干燥二甲基亚砜，室温搅拌20min后，加入53a(1.0g，3.08mmol)，加入CuI(88mg，0.462mmol)和L-脯氨酸(106mg，0.92mmol)，置换氮气三次，100℃反应16h。将反应体系冷却至室温，缓慢倾倒入饱和氯化铵水溶液中(220mL)，用乙酸乙酯萃取(50mL×2)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝58:42)，得53b(0.27g，收率：32％)。Add 3-ethynyl azetidine hydrochloride (540 mg, 4.59 mmol) and potassium carbonate (1.3 g, 9.41 mmol) into a 100 mL single-neck bottle, add 20 mL dry dimethyl sulfoxide, and stir at room temperature for 20 min. Add 53a (1.0g, 3.08mmol), add CuI (88mg, 0.462mmol) and L-proline (106mg, 0.92mmol), replace nitrogen three times, and react at 100°C for 16h. Cool the reaction system to room temperature, slowly pour it into saturated aqueous ammonium chloride solution (220mL), extract with ethyl acetate (50mL×2), wash the organic phase with saturated aqueous sodium chloride solution (50mL×2), and use anhydrous sodium sulfate. Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=58:42) to obtain 53b (0.27g, yield: 32%).
LCMS m/z＝278.1[M+1]+ LCMS m/z＝278.1[M+1] +
第三步：53c的制备Step 3: Preparation of 53c
将53b(0.27g，0.97mmol)溶于10mL二氯甲烷中，加入三氟乙酸(3mL)，室温反应16h。将反应体系减压浓缩，加入饱和碳酸钠水溶液(30ml)，用乙酸乙酯萃取(30mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝42:58)，得53c(100mg，收率：70％)。Dissolve 53b (0.27g, 0.97mmol) in 10mL dichloromethane, add trifluoroacetic acid (3mL), and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, added with saturated aqueous sodium carbonate solution (30 ml), extracted with ethyl acetate (30 mL × 3), washed the organic phase with saturated aqueous sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentrate, and the crude product is separated and purified by silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 42:58) to obtain 53c (100 mg, yield: 70%).
LCMS m/z＝148.1[M+1]+ LCMS m/z＝148.1[M+1] +
第四步：53d的制备Step 4: Preparation of 53d
将53c(100mg，0.68mmol)加入干燥乙腈(10mL)中、加入碳酸铯(442mg，1.36mmol)和53B(250mg，0.82mmol)，90℃反应16h。将反应体系冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:99)，得53d(90mg，收率：35％)。Add 53c (100 mg, 0.68 mmol) to dry acetonitrile (10 mL), add cesium carbonate (442 mg, 1.36 mmol) and 53B (250 mg, 0.82 mmol), and react at 90°C for 16 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:99) to obtain 53d (90 mg, yield: 35% ).
LCMS m/z＝374.1[M+1]+ LCMS m/z＝374.1[M+1] +
第五步：化合物53的制备 Step 5: Preparation of Compound 53
将53d(90mg，0.24mmol)加入干燥DMF(10.0mL)中，加入53C(67mg，0.2mmol)和三乙胺(61mg，0.6mmol)，置换氮气三次，加入PdCl2(PPh3)2(14mg，0.02mmol)和CuI(6mg，0.031mmol)，置换氮气三次，60℃反应3h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(80.0mL)，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝22:78)，得化合物53(50mg，收率：40％)。Add 53d (90 mg, 0.24 mmol) to dry DMF (10.0 mL), add 53C (67 mg, 0.2 mmol) and triethylamine (61 mg, 0.6 mmol), replace nitrogen three times, and add PdCl 2 (PPh 3 ) 2 (14 mg , 0.02mmol) and CuI (6mg, 0.031mmol), replaced with nitrogen three times, and reacted at 60°C for 3h. The reaction system was cooled to room temperature, saturated aqueous ammonium chloride solution (80.0 mL) was slowly added, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 2), and dried over anhydrous sodium sulfate. , concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 22:78) to obtain compound 53 (50 mg, yield: 40%).
1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.43–8.34(m,1H),7.98(s,1H),7.89–7.78(m,2H),7.76–7.71(m,1H),7.51–7.45(m,1H),7.38–7.33(m,1H),7.24–7.21(m,1H),7.15–7.11(m,1H),5.01–4.93(m,1H),4.19–4.06(m,2H),3.84–3.70(m,3H),2.98–2.67(m,3H),2.21–2.11(m,1H),1.98–1.90(m,6H),1.54–1.45(m,1H),1.05–0.96(m,2H),0.63–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.04(s,1H),8.43–8.34(m,1H),7.98(s,1H),7.89–7.78(m,2H),7.76–7.71(m,1H) ),7.51–7.45(m,1H),7.38–7.33(m,1H),7.24–7.21(m,1H),7.15–7.11(m,1H),5.01–4.93(m,1H),4.19–4.06 (m,2H),3.84–3.70(m,3H),2.98–2.67(m,3H),2.21–2.11(m,1H),1.98–1.90(m,6H),1.54–1.45(m,1H) ,1.05–0.96(m,2H),0.63–0.52(m,2H).
LCMS m/z＝630.2[M+1]+ LCMS m/z＝630.2[M+1] +
实施例54：化合物54的制备
Example 54: Preparation of Compound 54
以化合物54a为原料，参考实施例19得到化合物54(45mg)。Using compound 54a as a raw material, compound 54 (45 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.56(s,1H),8.11(dd,1H),8.08–7.97(m,1H),7.81(s,1H),7.75–7.62(m,2H),7.24–7.15(m,1H),7.11–7.06(m,1H),7.04–6.97(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),2.95–2.63(m,3H),2.18–2.07(m,1H),2.02–1.90(m,6H),1.56–1.45(m,1H),0.92–0.80(m,2H),0.60–0.45(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.56(s,1H),8.11(dd,1H),8.08–7.97(m,1H),7.81(s,1H),7.75–7.62(m,2H), 7.24–7.15(m,1H),7.11–7.06(m,1H),7.04–6.97(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H ),4.43–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),2.95–2.63(m,3H),2.18–2.07(m,1H),2.02–1.90 (m,6H),1.56–1.45(m,1H),0.92–0.80(m,2H),0.60–0.45(m,2H).
LCMS m/z＝605.3[M+1]+ LCMS m/z＝605.3[M+1] +
实施例55：化合物55的制备
Example 55: Preparation of Compound 55
第一步：55b的制备Step One: Preparation of 55b
将2-碘苯甲酸(0.45g,1.81mmol)、1-氯-N,N,2-三甲基丙烯胺(0.36g,2.69mmol)加入二氯甲烷(10mL)中，室温搅拌1h后，加入三乙胺(0.75mL)与2-氯-4-(三氟甲基)苯胺(0.42g,2.15mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20)，得到55b(0.33g，产率：43％)。 Add 2-iodobenzoic acid (0.45g, 1.81mmol) and 1-chloro-N,N,2-trimethylpropenylamine (0.36g, 2.69mmol) into dichloromethane (10mL), and stir at room temperature for 1 hour. Add triethylamine (0.75mL) and 2-chloro-4-(trifluoromethyl)aniline (0.42g, 2.15mmol), and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v)=1:20) to obtain 55b (0.33g, yield: 43%).
LCMS m/z＝425.9[M+1]+ LCMS m/z＝425.9[M+1] +
第二步：55c的制备Step 2: Preparation of 55c
将55b(0.20g,0.47mmol)、3-乙炔基氮杂环丁-1-甲酸叔丁酯(0.13g,0.72mmol)、PdCl2(PPh3)2(33mg,0.047mmol)、CuI(18mg,0.095mmol)和DIPEA(0.18g,1.39mmol)加入DMF(5mL)，氮气氛围60℃反应5h。将反应体系冷却至室温，加入水(20mL)中，用乙酸乙酯/甲醇(v/v)＝5:1的混合溶剂萃取(20mL×3)，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到55c(0.22g，收率：98％)。55b (0.20g, 0.47mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.13g, 0.72mmol), PdCl 2 (PPh 3 ) 2 (33mg, 0.047mmol), CuI (18mg ,0.095mmol) and DIPEA (0.18g, 1.39mmol) were added to DMF (5mL), and the reaction was carried out at 60°C for 5h in a nitrogen atmosphere. Cool the reaction system to room temperature, add water (20 mL), extract with a mixed solvent of ethyl acetate/methanol (v/v) = 5:1 (20 mL × 3), combine the organic phases, and use anhydrous sodium sulfate for the organic phase. Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain 55c (0.22g, yield: 98%).
以化合物55c为原料，参考实施例23得到化合物55(18mg)。Using compound 55c as a raw material, compound 55 (18 mg) was obtained with reference to Example 23.
1H NMR(400MHz,CDCl3)δ8.07–7.97(m,2H),7.93–7.80(m,2H),7.79–7.69(m,2H),7.68–7.61(m,2H),7.58–7.50(m,1H),6.79(d,1H),6.54(dd,1H),4.98–4.87(m,1H),4.55–4.32(m,3H),3.92–3.80(m,2H),2.95–2.63(m,3H),2.19–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.07–7.97(m,2H),7.93–7.80(m,2H),7.79–7.69(m,2H),7.68–7.61(m,2H),7.58–7.50 (m,1H),6.79(d,1H),6.54(dd,1H),4.98–4.87(m,1H),4.55–4.32(m,3H),3.92–3.80(m,2H),2.95–2.63 (m,3H),2.19–2.07(m,1H).
实施例56：化合物56的制备
Example 56: Preparation of Compound 56
以化合物56a为原料，参考实施例22得到化合物56(50mg)。Using compound 56a as a raw material, compound 56 (50 mg) was obtained with reference to Example 22.
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.44(d,1H),7.96(s,1H),7.85–7.73(m,3H),7.72–7.63(m,2H),6.81(d,1H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),3.12–2.98(m,2H),2.96–2.64(m,5H),2.30–2.20(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.62(s,1H),8.44(d,1H),7.96(s,1H),7.85–7.73(m,3H),7.72–7.63(m,2H), 6.81(d,1H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H), 3.12–2.98(m,2H),2.96–2.64(m,5H),2.30–2.20(m,3H).
实施例57：化合物57的制备
Example 57: Preparation of Compound 57
第一步：57b的制备Step One: Preparation of 57b
将57a(1.95g，10.05mmol)加入到30mL超干DMF中，冷却至5℃，加入60％氢化钠(0.29g)，在5℃下反应1h后，加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(3.0g，10.87mmol)，60℃反应3h。将反应体系冷却至室温，加入100mL水，析出固体，过滤，将滤饼减压干燥，得粗品57b(2.1g)。 Add 57a (1.95g, 10.05mmol) to 30mL of ultra-dry DMF, cool to 5°C, add 60% sodium hydride (0.29g), react at 5°C for 1 hour, then add 2-(2,6-dioxo Piperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3.0g, 10.87mmol) was reacted at 60°C for 3 hours. The reaction system was cooled to room temperature, 100 mL of water was added, the solid was precipitated, filtered, and the filter cake was dried under reduced pressure to obtain crude product 57b (2.1 g).
LCMS m/z＝451.3[M+1]+ LCMS m/z＝451.3[M+1] +
第二步：57d的制备Step 2: Preparation of 57d
将2c(4.7g，10mmol)溶于100mL二氯甲烷中，依次加入乙炔基三甲基硅烷(1.96g，20mmol)、TEA(2.0g，19.8mmol)、CuI(0.19g，1mmol)和PdCl2(PPh3)2(0.7g，1mmol)，置换氮气三次，室温反应4h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得57d(4.3g，收率：98％)。Dissolve 2c (4.7g, 10mmol) in 100mL dichloromethane, and add ethynyltrimethylsilane (1.96g, 20mmol), TEA (2.0g, 19.8mmol), CuI (0.19g, 1mmol) and PdCl 2 in sequence. (PPh 3 ) 2 (0.7g, 1mmol), replaced with nitrogen three times, and reacted at room temperature for 4 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 57d (4.3 g, yield: 98%).
第三步：57e的制备Step 3: Preparation of 57e
将57d(4.3g，9.77mmol)加入到60mL四氢呋喃中，加入20mL 1mol/L四丁基氟化铵的四氢呋喃溶液，室温反应2h。向反应液中加入100mL乙酸乙酯，用100mL水洗涤三次，无水硫酸钠干燥，减压浓缩，得粗品57e(3.5g)。Add 57d (4.3g, 9.77mmol) to 60mL tetrahydrofuran, add 20mL of 1mol/L tetrabutylammonium fluoride solution in tetrahydrofuran, and react at room temperature for 2h. 100 mL of ethyl acetate was added to the reaction solution, washed three times with 100 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 57e (3.5 g).
第四步：化合物57的制备Step 4: Preparation of Compound 57
将上述粗品57e(0.22g)溶于5mL DMF中，依次加入上述粗品57b(0.27g)、TEA(0.2g，1.98mmol)、CuI(0.019g，0.1mmol)和PdCl2(PPh3)2(0.07g，0.1mmol)，置换氮气三次，65℃反应4h。将反应液冷却至室温，加入20mL饱和氯化铵水溶液，过滤，将滤饼用10mL水洗涤，将滤饼用50mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得化合物57(150mg，从化合物57d算两步收率：35％)。The above crude product 57e (0.22g) was dissolved in 5mL DMF, and the above crude product 57b (0.27g), TEA (0.2g, 1.98mmol), CuI (0.019g, 0.1mmol) and PdCl 2 (PPh 3 ) 2 ( 0.07g, 0.1mmol), replaced with nitrogen three times, and reacted at 65°C for 4 hours. Cool the reaction solution to room temperature, add 20 mL of saturated aqueous ammonium chloride solution, filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 50 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column. (Petroleum ether/ethyl acetate (v/v)=1:1), compound 57 (150 mg, two-step yield calculated from compound 57d: 35%) was obtained.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.20–9.08(m,2H),8.50(s,1H),8.45–8.32(m,2H),8.23–8.04(m,3H),8.04–7.87(m,2H),7.80–7.71(m,1H),5.26–5.12(m,1H),3.05–2.73(m,5H),2.70–2.50(m,2H),2.18–1.92(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.13(s,1H),9.20–9.08(m,2H),8.50(s,1H),8.45–8.32(m,2H),8.23–8.04(m ,3H),8.04–7.87(m,2H),7.80–7.71(m,1H),5.26–5.12(m,1H),3.05–2.73(m,5H),2.70–2.50(m,2H),2.18 –1.92(m,3H).
实施例58：化合物58的制备
Example 58: Preparation of Compound 58
第一步：58a的制备Step One: Preparation of 58a
将上述粗品57e(0.74g)加入到12mL四氢呋喃中，加入1-Boc-3-叠氮基氮杂环丁烷(CAS:429672-02-6)(0.4g，2.02mmol)，加入五水硫酸铜(1.0g，4.0mmol)和L-抗坏血酸钠(CAS:134-03-2)(0.4g，2.02mmol)，室温反应16h。向反应体系中加入50mL水，析出固体，用50mL乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得58a(0.9g，收率：79％)。Add the above crude product 57e (0.74g) to 12mL tetrahydrofuran, add 1-Boc-3-azidoazetidine (CAS: 429672-02-6) (0.4g, 2.02mmol), and add sulfuric acid pentahydrate Copper (1.0g, 4.0mmol) and L-sodium ascorbate (CAS: 134-03-2) (0.4g, 2.02mmol) were reacted at room temperature for 16 hours. Add 50 mL of water to the reaction system, precipitate the solid, extract with 50 mL of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1: 1), 58a (0.9g, yield: 79%) was obtained.
LCMS m/z＝566.2[M+1]+ LCMS m/z＝566.2[M+1] +
第二步：58b的对甲苯磺酸盐的制备Step 2: Preparation of p-toluenesulfonate of 58b
将58a(0.28g，0.495mmol)加入到5mL乙腈中，加入对甲苯磺酸一水合物(0.38g，2.0mmol)，室温反应3h。将反应体系减压浓缩，得粗品58b的对甲苯磺酸盐(0.23g)。 Add 58a (0.28g, 0.495mmol) to 5 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.38g, 2.0mmol), and react at room temperature for 3 hours. The reaction system was concentrated under reduced pressure to obtain crude product 58b p-toluenesulfonate (0.23g).
第三步：化合物58的制备Step 3: Preparation of Compound 58
将上述粗品58b的对甲苯磺酸盐(0.23g)溶于5mL DMSO中，加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(280mg，1.01mmol)，95℃反应3h。将反应液冷却至室温，加入20mL水，析出固体，抽滤，将滤饼用50mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝15:1)，得化合物58(110mg，收率：15％)。Dissolve the p-toluenesulfonate salt (0.23g) of the above crude product 58b in 5mL DMSO, add 1.0mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline -1,3-dione (280 mg, 1.01 mmol), react at 95°C for 3 hours. Cool the reaction solution to room temperature, add 20 mL of water, precipitate the solid, filter with suction, dissolve the filter cake with 50 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (methylene chloride/methanol). (v/v)=15:1), compound 58 (110 mg, yield: 15%) was obtained.
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.12(s,1H),8.63(s,1H),8.47(s,1H),8.23(d,1H),8.10(s,1H),7.94–7.88(m,1H),7.78–7.68(m,2H),6.98(d,1H),6.82(dd,1H),5.82–5.70(m,1H),5.14–5.02(m,1H),4.73–4.60(m,2H),4.48–4.37(m,2H),3.05–2.73(m,5H),2.71–2.50(m,2H),2.10–1.95(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.07(s,1H),9.12(s,1H),8.63(s,1H),8.47(s,1H),8.23(d,1H),8.10( s,1H),7.94–7.88(m,1H),7.78–7.68(m,2H),6.98(d,1H),6.82(dd,1H),5.82–5.70(m,1H),5.14–5.02( m,1H),4.73–4.60(m,2H),4.48–4.37(m,2H),3.05–2.73(m,5H),2.71–2.50(m,2H),2.10–1.95(m,3H).
LCMS m/z＝722.6[M+1]+ LCMS m/z＝722.6[M+1] +
实施例59：化合物59的合成
Example 59: Synthesis of Compound 59
第一步：59b的制备Step One: Preparation of 59b
将59a(2.26g，9.96mmol)加入到40mL 1,4-二氧六环中，加入乙烯基硼酸频哪醇酯(3.1g，20.1mmol)和氟化铯(3.0g，19.75mmol)，加入Pd(dppf)Cl2(0.7g，0.96mmol)和10mL水，85℃反应16h。将反应体系冷却至室温，减压浓缩，加入100ml乙酸乙酯和50mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝10:1)，得59b(1.0g，收率：58％)。Add 59a (2.26g, 9.96mmol) to 40mL of 1,4-dioxane, add vinylboronic acid pinacol ester (3.1g, 20.1mmol) and cesium fluoride (3.0g, 19.75mmol), add Pd(dppf)Cl 2 (0.7g, 0.96mmol) and 10mL water were reacted at 85°C for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 100 ml of ethyl acetate and 50 mL of water were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v)=10:1), 59b (1.0g, yield: 58%) was obtained.
第二步：59c的制备Step 2: Preparation of 59c
将59b(1.0g，5.74mmol)加入到20mL四氢呋喃中，加入碘化钠(0.15g，1.0mmol)和三氟甲基三甲基硅烷(3.3g，23.2mmol)，65℃反应5h。将反应体系冷却至室温，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝1:1)，得59c(0.5g，收率：39％)。Add 59b (1.0g, 5.74mmol) to 20mL tetrahydrofuran, add sodium iodide (0.15g, 1.0mmol) and trifluoromethyltrimethylsilane (3.3g, 23.2mmol), and react at 65°C for 5h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=1:1) to obtain 59c (0.5g, yield: 39%).
第三步：59d的制备Step 3: Preparation of 59d
将59c(0.22g，0.98mmol)加入到10mL乙醇中，加入铁粉(0.34g，6.07mmol)和2mL饱和氯化铵水溶液，回流反应2h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，得粗品59d(0.16g)。Add 59c (0.22g, 0.98mmol) to 10mL ethanol, add iron powder (0.34g, 6.07mmol) and 2mL saturated aqueous ammonium chloride solution, and reflux for 2h. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 59d (0.16 g).
LCMS m/z＝195.1[M+1]+ LCMS m/z＝195.1[M+1] +
以化合物59d为原料，参考实施例19得到化合物59(0.19g)。Using compound 59d as a raw material, compound 59 (0.19g) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.29(d,1H),8.09(s,1H),7.80(s,1H),7.75(s,1H),7.67(d,1H),7.58(dd,1H),7.49(s,1H),6.80(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30 (m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),2.95–2.62(m,3H),2.54–2.41(m,1H),2.04–1.88(m,7H),1.70–1.50(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.30(s,1H),8.29(d,1H),8.09(s,1H),7.80(s,1H),7.75(s,1H),7.67(d, 1H),7.58(dd,1H),7.49(s,1H),6.80(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30 (m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),2.95–2.62(m,3H),2.54–2.41(m,1H),2.04–1.88(m,7H) ,1.70–1.50(m,2H).
实施例60：化合物60的制备
Example 60: Preparation of Compound 60
以化合物60a为原料，参考实施例59得到化合物60(55mg)。Using compound 60a as a raw material, compound 60 (55 mg) was obtained with reference to Example 59.
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.28–8.14(m,2H),7.81(s,1H),7.75(s,1H),7.67(d,1H),7.54(d,1H),7.45(s,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.01(m,2H),3.86–3.74(m,1H),2.94–2.62(m,3H),2.60–2.46(m,1H),2.18–2.06(m,1H),2.00–1.86(m,7H),1.62–1.49(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ9.06(s,1H),8.28–8.14(m,2H),7.81(s,1H),7.75(s,1H),7.67(d,1H),7.54( d,1H),7.45(s,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.01( m,2H),3.86–3.74(m,1H),2.94–2.62(m,3H),2.60–2.46(m,1H),2.18–2.06(m,1H),2.00–1.86(m,7H), 1.62–1.49(m,1H).
实施例61：化合物61的三氟乙酸盐的制备
Example 61: Preparation of trifluoroacetate salt of compound 61
第一步：61b的制备Step One: Preparation of 61b
将61a(2.41g，9.88mmol)和1-溴环丁烷-1-甲酸乙酯(1.5g，7.24mmol)溶于40mL乙腈中，加入碳酸铯(4.39g，13.47mmol)，80℃反应18h。将反应液冷却至室温，抽滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得61b(1.1g，收率：41％)。Dissolve 61a (2.41g, 9.88mmol) and ethyl 1-bromocyclobutane-1-carboxylate (1.5g, 7.24mmol) in 40mL acetonitrile, add cesium carbonate (4.39g, 13.47mmol), and react at 80°C for 18h . The reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 61b (1.1g, yield: 41%).
LCMS m/z＝371.4[M+1]+ LCMS m/z＝371.4[M+1] +
第二步：61c的制备Step 2: Preparation of 61c
将61b(1.1g，2.97mmol)溶于10mL四氢呋喃/水(v/v)＝4:1中，加入一水合氢氧化锂(0.62g，14.78mmol)，40℃反应5h。将反应液冷却至室温，加入5mL水，用1mol/L盐酸溶液调pH至3，用20mL乙酸乙酯萃取三次，分离出有机相，无水硫酸钠干燥，减压浓缩，得粗品(0.99g)。将上述粗品(0.99g)溶于10mL DCM中，加入TCFH(1.22g，4.35mmol)和2-氯-4-(三氟甲基)苯胺(0.73g，3.73mmol)，加入N-甲基咪唑(0.95g，11.57mmol)，室温反应19h。向反应液中加入30mL二氯甲烷，加入30mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1-1:1)，得到61c(650mg，收率：42％)。Dissolve 61b (1.1g, 2.97mmol) in 10 mL tetrahydrofuran/water (v/v) = 4:1, add lithium hydroxide monohydrate (0.62g, 14.78mmol), and react at 40°C for 5 hours. Cool the reaction solution to room temperature, add 5 mL of water, adjust the pH to 3 with 1 mol/L hydrochloric acid solution, extract three times with 20 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (0.99 g ). Dissolve the above crude product (0.99g) in 10mL DCM, add TCFH (1.22g, 4.35mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.73g, 3.73mmol), add N-methylimidazole (0.95g, 11.57mmol), reacted at room temperature for 19h. Add 30 mL of methylene chloride to the reaction solution, add 30 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5 :1-1:1) to obtain 61c (650 mg, yield: 42%).
第三步：化合物61的三氟乙酸盐的制备Step 3: Preparation of trifluoroacetate salt of compound 61
将61c(0.40g，0.77mmol)、上述粗品中间体1(0.39g)、TEA(0.23g，2.27mmol)、CuI(29mg， 0.15mmol)和PdCl2(PPh3)2(110mg，0.157mmol)加入5mL DMF，氮气氛围55℃反应5h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用50mL二氯甲烷/甲醇(v/v)＝5:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1.5)，所得粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得到化合物61的三氟乙酸盐(210mg)。61c (0.40g, 0.77mmol), the above crude intermediate 1 (0.39g), TEA (0.23g, 2.27mmol), CuI (29mg, 0.15mmol) and PdCl 2 (PPh 3 ) 2 (110mg, 0.157mmol) were added with 5mL DMF, and the reaction was carried out at 55°C in a nitrogen atmosphere for 5h. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 50 mL of a mixed solvent of methylene chloride/methanol (v/v) = 5:1, and dry over anhydrous sodium sulfate. , concentrated under reduced pressure, the crude product was separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:1.5), and the crude product obtained was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase , the preparation column model is Sunfire C18, 5μm, inner diameter × length = 30mm × 150mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 61 (210 mg).
1H NMR(400MHz,CDCl3)δ9.16(s,1H),8.63(d,1H),7.96(s,1H),7.83–7.75(m,1H),7.70(d,1H),7.55–7.38(m,4H),7.30–7.20(m,1H),6.86(d,1H),6.61(dd,1H),5.24–5.10(m,1H),5.01–4.87(m,1H),4.53–4.41(m,2H),4.30–4.17(m,2H),4.17–3.93(m,2H),2.97–2.36(m,6H),2.36–2.21(m,1H),2.21–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ9.16(s,1H),8.63(d,1H),7.96(s,1H),7.83–7.75(m,1H),7.70(d,1H),7.55– 7.38(m,4H),7.30–7.20(m,1H),6.86(d,1H),6.61(dd,1H),5.24–5.10(m,1H),5.01–4.87(m,1H),4.53– 4.41(m,2H),4.30–4.17(m,2H),4.17–3.93(m,2H),2.97–2.36(m,6H),2.36–2.21(m,1H),2.21–2.07(m,1H ).
实施例62：化合物62的三氟乙酸盐的制备
Example 62: Preparation of trifluoroacetate salt of compound 62
第一步：62b的制备Step One: Preparation of 62b
将62a(0.65g，2.90mmol)溶于10mL DCM中，加入DMAP(71mg，0.58mmol)和(Boc)2O(0.69g，3.16mmol)，室温反应4h。向反应液中加入20mL二氯甲烷和30mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1-1:1)，得到62b(0.8g，收率：85％)。Dissolve 62a (0.65g, 2.90mmol) in 10mL DCM, add DMAP (71mg, 0.58mmol) and (Boc) 2 O (0.69g, 3.16mmol), and react at room temperature for 4h. Add 20 mL dichloromethane and 30 mL water to the reaction solution, separate the organic phase, dry it over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5: 1-1:1), 62b (0.8g, yield: 85%) was obtained.
第二步：62c的制备Step 2: Preparation of 62c
将62b(0.4g，1.23mmol)、氰化锌(0.14g，1.19mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(CAS:161265-03-8)(71mg，0.12mmol)和双(二亚芐基丙酮)钯(CAS:32005-36-0)(71mg，0.125mmol)溶于5mL DMF中，加入N,N,N',N'-四甲基乙二胺(0.57g，4.91mmol)，100℃反应18h。将反应液冷却至室温，加入50mL饱和氯化钠水溶液，用60mL乙酸乙酯萃取，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得62c(0.22g，收率：68％)。Combine 62b (0.4g, 1.23mmol), zinc cyanide (0.14g, 1.19mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (CAS: 161265-03-8) (71mg, 0.12mmol) and bis(dibenzylideneacetone)palladium (CAS:32005-36-0) (71mg, 0.125mmol) were dissolved in 5mL DMF, and N,N,N',N'-tetramethyl Ethylenediamine (0.57g, 4.91mmol), reacted at 100°C for 18h. The reaction solution was cooled to room temperature, 50 mL of saturated sodium chloride aqueous solution was added, extracted with 60 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ Ethyl acetate (v/v)=5:1) to obtain 62c (0.22g, yield: 68%).
LCMS m/z＝271.4[M+1]+ LCMS m/z＝271.4[M+1] +
第三步：62d的制备Step 3: Preparation of 62d
将62c(0.22g，0.81mmol)溶于2mL DCM中，加入2mL三氟乙酸，室温反应3.5h。向反应液中加入5mL水，用饱和碳酸氢钠水溶液调pH至8，用20mL二氯甲烷萃取三次，分离出有机相，无水硫酸钠干燥，减压浓缩，得粗品62d(0.11g)。Dissolve 62c (0.22g, 0.81mmol) in 2mL DCM, add 2mL trifluoroacetic acid, and react at room temperature for 3.5h. Add 5 mL of water to the reaction solution, adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, extract three times with 20 mL of dichloromethane, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 62d (0.11 g).
以62d+2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸为原料，参考实施例7的合成方法得到化合物62的三氟乙酸盐(19mg)。 Using 62d+2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw material, the trifluoroacetate salt of compound 62 (19 mg) was obtained with reference to the synthesis method of Example 7.
1H NMR(400MHz,CDCl3)δ8.35(d,1H),8.00(s,1H),7.72–7.59(m,3H),7.48(dd,1H),6.82(dd,2H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.27(m,2H),4.13–4.01(m,2H),3.88–3.72(m,1H),3.10(s,2H),2.95–2.69(m,3H),2.18–2.07(m,1H),1.87(s,6H),1.04–0.84(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.35(d,1H),8.00(s,1H),7.72–7.59(m,3H),7.48(dd,1H),6.82(dd,2H),6.55( dd,1H),4.98–4.88(m,1H),4.43–4.27(m,2H),4.13–4.01(m,2H),3.88–3.72(m,1H),3.10(s,2H),2.95– 2.69(m,3H),2.18–2.07(m,1H),1.87(s,6H),1.04–0.84(m,4H).
LCMS m/z＝642.3[M+1]+ LCMS m/z＝642.3[M+1] +
实施例63：化合物63的三氟乙酸盐的制备
Example 63: Preparation of trifluoroacetate salt of compound 63
以化合物63a+2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸为原料，参考实施例19得到化合物63的三氟乙酸盐(110mg)Using compound 63a+2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw materials, the trifluoroacetate salt of compound 63 (110 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.10–8.02(m,1H),7.91(s,1H),7.76(s,1H),7.71(s,1H),7.60(d,1H),7.21–7.13(m,2H),6.77–6.70(m,1H),6.48(dd,1H),4.91–4.81(m,1H),4.33–4.22(m,2H),4.05–3.95(m,2H),3.80–3.67(m,1H),2.90–2.57(m,3H),2.12–2.00(m,1H),1.87(s,6H),1.83–1.73(m,1H),0.97–0.88(m,2H),0.61–0.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.12(s,1H),8.10–8.02(m,1H),7.91(s,1H),7.76(s,1H),7.71(s,1H),7.60( d,1H),7.21–7.13(m,2H),6.77–6.70(m,1H),6.48(dd,1H),4.91–4.81(m,1H),4.33–4.22(m,2H),4.05– 3.95(m,2H),3.80–3.67(m,1H),2.90–2.57(m,3H),2.12–2.00(m,1H),1.87(s,6H),1.83–1.73(m,1H), 0.97–0.88(m,2H),0.61–0.54(m,2H).
LCMS m/z＝630.2[M+1]+ LCMS m/z＝630.2[M+1] +
实施例64：化合物64的制备
Example 64: Preparation of Compound 64
第一步：64b的制备Step 1: Preparation of 64b
将64a(3.52g，20.0mmol)、三苯基膦(15.73g，59.97mmol)、碘化钾(6.64g，40.0mmol)加入60mL乙腈中，氮气氛围70℃反应30min,冷却至室温，缓慢滴加2,2-二氟-2-(氟磺酰基)乙酸甲酯(6.72g，34.98mmol)的20mL乙腈溶液，氮气氛围70℃反应3h。将反应体系冷却到室温，加入80mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(纯石油醚)，得到64b(0.34g，收率：7％)。Add 64a (3.52g, 20.0mmol), triphenylphosphine (15.73g, 59.97mmol), and potassium iodide (6.64g, 40.0mmol) into 60mL acetonitrile, react at 70°C for 30min in a nitrogen atmosphere, cool to room temperature, and slowly add 2 drops , 20 mL acetonitrile solution of 2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (6.72g, 34.98mmol), reacted at 70°C for 3 hours in a nitrogen atmosphere. The reaction system was cooled to room temperature, 80 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (pure petroleum ether) to obtain 64b (0.34g, yield: 7%).
第二步：64c的制备Step 2: Preparation of 64c
将64b(0.2g，0.87mmol)溶于5mL乙醇中，加入2mL饱和氯化铵水溶液和还原铁粉(0.49g，8.75mmol)，回流反应2h。将反应体系冷却至室温，过滤，将滤液用100mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得64c(0.16g，收率：92％)。Dissolve 64b (0.2g, 0.87mmol) in 5mL of ethanol, add 2mL of saturated aqueous ammonium chloride solution and reduced iron powder (0.49g, 8.75mmol), and react under reflux for 2h. The reaction system was cooled to room temperature and filtered. The filtrate was extracted with 100 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) =5:1), 64c (0.16g, yield: 92%) was obtained.
LCMS m/z＝201.1[M+1]+ LCMS m/z＝201.1[M+1] +
以化合物64c为原料，参考实施例19得到化合物64(0.110g)。Using compound 64c as a raw material, compound 64 (0.110 g) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ9.25(s,1H),8.15(d,1H),7.98(s,1H),7.83–7.75(m,2H),7.71–7.60(m,2H),7.58–7.52(m,1H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.01(m,2H),3.88–3.75(m,1H),3.30(q,2H),2.95–2.65(m,3H),2.17–2.06(m,1H),1.93(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.25(s,1H),8.15(d,1H),7.98(s,1H),7.83–7.75(m,2H),7.71–7.60(m,2H), 7.58–7.52(m,1H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.01(m,2H), 3.88–3.75(m,1H),3.30(q,2H),2.95–2.65(m,3H),2.17–2.06(m,1H),1.93(s,6H).
实施例65：化合物65三氟乙酸盐的制备
Example 65: Preparation of compound 65 trifluoroacetate salt
以65b为原料，参考实施例19制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物65的三氟乙酸盐(20mg)。Use 65b as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 65 (20 mg).
化合物65的游离碱以化合物65b为原料，参考实施例19的制备方法，经中性制备[流动相体系：乙腈/水(含10mmol/L碳酸氢铵)]冻干得到。The free base of compound 65 was obtained by freeze-drying using compound 65b as raw material, referring to the preparation method of Example 19, and neutral preparation [mobile phase system: acetonitrile/water (containing 10 mmol/L ammonium bicarbonate)].
化合物65游离碱核磁数据：Compound 65 free base NMR data:
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.02(s,1H),7.96(d,1H),7.80(s,1H),7.70(s,1H),7.67(d,1H),6.88(dd,1H),6.84–6.77(m,2H),6.55(dd,1H),4.99–4.88(m,1H),4.40–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),2.94–2.64(m,3H),2.20–2.05(m,1H),1.94(s,6H),1.85–1.73(m,1H),1.53–1.41(m,1H),0.95–0.77(m,4H),0.65–0.55(m,2H),0.55–0.47(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.43(s,1H),8.02(s,1H),7.96(d,1H),7.80(s,1H),7.70(s,1H),7.67(d, 1H),6.88(dd,1H),6.84–6.77(m,2H),6.55(dd,1H),4.99–4.88(m,1H),4.40–4.30(m,2H),4.13–4.00(m, 2H),3.88–3.73(m,1H),2.94–2.64(m,3H),2.20–2.05(m,1H),1.94(s,6H),1.85–1.73(m,1H),1.53–1.41( m,1H),0.95–0.77(m,4H),0.65–0.55(m,2H),0.55–0.47(m,2H).
LCMS m/z＝645.3[M+1]+ LCMS m/z＝645.3[M+1] +
实施例66：化合物66的制备
Example 66: Preparation of Compound 66
第一步：66c的制备Step One: Preparation of 66c
向反应瓶中分别加入1-氯-N,N,2-三甲基丙烯胺(0.72g,5.39mmol)、2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸(1.00g,3.57mmol)和DCM(20mL)，室温搅拌1h后，依次加入TEA(1.48mL,10.65mmol)和66b(0.56g,3.54mmol)，室温反应1h。将反应液减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:5)，得66c(1.05g，收率：71％)。Add 1-chloro-N,N,2-trimethylpropenylamine (0.72g, 5.39mmol) and 2-(4-iodo-1H-pyrazol-1-yl)-2-methyl to the reaction bottle respectively. Propionic acid (1.00g, 3.57mmol) and DCM (20mL) were stirred at room temperature for 1 h, then TEA (1.48mL, 10.65mmol) and 66b (0.56g, 3.54mmol) were added in sequence, and the reaction was carried out at room temperature for 1h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:5) to obtain 66c (1.05 g, yield: 71%).
LCMS m/z＝421.0[M+1]+ LCMS m/z＝421.0[M+1] +
第二步：66e的制备 Step 2: Preparation of 66e
将66d(7.6g，49.96mmol)溶于100mL DMSO中，加入DIPEA(16.15g，125.00mmol)和3-乙炔基氮杂环丁烷盐酸盐(8.82g，75.01mmol)，120℃反应3h。将反应液冷却至室温，将反应体系缓慢倒入800mL水中，过滤，收集滤饼，将滤饼用20mL水洗涤，将滤饼鼓风干燥，得粗品66e(6.9g)。Dissolve 66d (7.6g, 49.96mmol) in 100mL DMSO, add DIPEA (16.15g, 125.00mmol) and 3-ethynyl azetidine hydrochloride (8.82g, 75.01mmol), and react at 120°C for 3 hours. Cool the reaction solution to room temperature, slowly pour the reaction system into 800 mL of water, filter, collect the filter cake, wash the filter cake with 20 mL of water, and air-dry the filter cake to obtain crude product 66e (6.9 g).
第三步：66f的制备Step 3: Preparation of 66f
将上述粗品66e(6.5g)悬浮于100mL THF、50mL甲醇与50mL水的混合溶剂中，加入一水合氢氧化锂(3.84g,91.52mmol)，室温反应16h。将反应体系减压浓缩，向残留物中加入100mL水，用浓盐酸调体系pH至3，析出固体，过滤，收集滤饼，将滤饼用20mL水洗涤，将滤饼鼓风干燥，得粗品66f(5.8g)。The above crude product 66e (6.5g) was suspended in a mixed solvent of 100mL THF, 50mL methanol and 50mL water, added lithium hydroxide monohydrate (3.84g, 91.52mmol), and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, 100 mL of water was added to the residue, the pH of the system was adjusted to 3 with concentrated hydrochloric acid, the solid was precipitated, filtered, and the filter cake was collected, the filter cake was washed with 20 mL of water, and the filter cake was air-dried to obtain a crude product. 66f(5.8g).
LCMS m/z＝232.2[M+1]+ LCMS m/z＝232.2[M+1] +
第四步：66g的制备Step 4: Preparation of 66g
将上述粗品66f(5.8g)溶解于200mL DCM中，加入咪唑(5.13g，75.35mmol)，冷却至0℃，缓慢分批加入TBSCl(5.67g，37.62mmol)，室温反应16h。向反应体系里加入200mL水，用浓盐酸调体系pH至3，用100mL DCM萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到66g(8.5g，从化合物66d算三步收率：52％)。Dissolve the above crude product 66f (5.8g) in 200mL DCM, add imidazole (5.13g, 75.35mmol), cool to 0°C, slowly add TBSCl (5.67g, 37.62mmol) in batches, and react at room temperature for 16h. Add 200 mL of water to the reaction system, adjust the pH of the system to 3 with concentrated hydrochloric acid, extract with 100 mL of DCM, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane). /methanol (v/v)=15:1), 66 g (8.5 g, three-step yield calculated from compound 66d: 52%) was obtained.
LCMS m/z＝346.2[M+1]+ LCMS m/z＝346.2[M+1] +
第五步：66h的制备Step 5: Preparation for 66h
将66g(7.5g，21.73mmol)溶于80mL DMF中，加入HATU(0.51g，1.34mmol)和DIPEA(11.22g，86.81mmol)，室温反应30min后，加入3-氨基哌啶-2,6-二酮盐酸盐(4.29g，26.06mmol)，室温反应16h。向反应体系里加入250mL水，用200mL DCM萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到66h(6.2g，收率：63％)。Dissolve 66g (7.5g, 21.73mmol) in 80mL DMF, add HATU (0.51g, 1.34mmol) and DIPEA (11.22g, 86.81mmol), react at room temperature for 30 minutes, then add 3-aminopiperidine-2,6- Dione hydrochloride (4.29g, 26.06mmol), reacted at room temperature for 16h. Add 250mL of water to the reaction system, extract with 200mL of DCM, wash the organic phase with 50mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/methanol (v/v) = 15 :1), obtained 66h (6.2g, yield: 63%).
LCMS m/z＝456.3[M+1]+ LCMS m/z＝456.3[M+1] +
第六步：66i的制备Step 6: Preparation of 66i
将66h(6.2g,13.62mmol)溶解在100mL THF中，加入四丁基氟化铵三水合物(6.44g，20.41mmol)，室温反应0.5h。将反应液减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:2)，得66i(4.0g，收率：86％)。Dissolve 66h (6.2g, 13.62mmol) in 100mL THF, add tetrabutylammonium fluoride trihydrate (6.44g, 20.41mmol), and react at room temperature for 0.5h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:2) to obtain 66i (4.0 g, yield: 86%).
第七步：66j的制备Step 7: Preparation of 66j
将66i(4.0g,11.72mmol)溶解在200mL DCM中，加入三乙胺(4.74g，46.84mmol)，加入对甲苯磺酰氯(2.9g，15.21mmol)，40℃反应16h。将反应液冷却至室温，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得66j(3.3g，收率：87％)。Dissolve 66i (4.0g, 11.72mmol) in 200mL DCM, add triethylamine (4.74g, 46.84mmol), add p-toluenesulfonyl chloride (2.9g, 15.21mmol), and react at 40°C for 16h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 15:1) to obtain 66j (3.3 g, yield: 87%).
LCMS m/z＝324.1[M+1]+ LCMS m/z＝324.1[M+1] +
第八步：化合物66的制备Step 8: Preparation of compound 66
将66j(0.2g，0.62mmol)与66c(0.39g，0.93mmol)溶于8mL DMF中，加入TEA(0.19g，1.88mmol)，置换氮气三次，加入CuI(12mg，0.063mmol)和PdCl2(PPh3)2(44mg，0.063mmol)，置换氮气三次，50℃反应1.5h。将反应液冷却至室温，加入60mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸 乙酯(v/v)＝1:2)，得到化合物66(0.065g，收率：17％)。Dissolve 66j (0.2g, 0.62mmol) and 66c (0.39g, 0.93mmol) in 8mL DMF, add TEA (0.19g, 1.88mmol), replace nitrogen three times, add CuI (12mg, 0.063mmol) and PdCl 2 ( PPh 3 ) 2 (44 mg, 0.063 mmol), replaced with nitrogen three times, and reacted at 50°C for 1.5 h. The reaction solution was cooled to room temperature, 60 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v)=1:2) to obtain compound 66 (0.065g, yield: 17%).
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.37(d,1H),7.87–7.76(m,2H),7.71(s,1H),7.49(dd,1H),7.40–7.35(m,1H),6.47(dd,1H),6.32–6.26(m,1H),5.41–5.24(m,2H),4.77–4.69(m,1H),4.37–4.24(m,2H),4.07–3.94(m,2H),3.84–3.70(m,1H),3.02–2.87(m,1H),2.73–2.15(m,3H),1.95(s,6H),1.57–1.44(m,1H),1.03–0.92(m,2H),0.61–0.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.09(s,1H),8.37(d,1H),7.87–7.76(m,2H),7.71(s,1H),7.49(dd,1H),7.40– 7.35(m,1H),6.47(dd,1H),6.32–6.26(m,1H),5.41–5.24(m,2H),4.77–4.69(m,1H),4.37–4.24(m,2H), 4.07–3.94(m,2H),3.84–3.70(m,1H),3.02–2.87(m,1H),2.73–2.15(m,3H),1.95(s,6H),1.57–1.44(m,1H ),1.03–0.92(m,2H),0.61–0.54(m,2H).
LCMS m/z＝616.8[M+1]+ LCMS m/z＝616.8[M+1] +
实施例67：化合物67的制备
Example 67: Preparation of Compound 67
第一步：67c的制备Step One: Preparation of 67c
将67A(2.95g，10.68mmol)溶于50mL DMSO中，加入上述粗品67b的盐酸盐(1.7g)，加入DIPEA(4.14g，32.03mmol)，80℃反应3h。将反应体系冷却至室温，缓慢倒入400mL水中，过滤，滤饼用20mL水洗涤，将滤饼减压干燥，得粗品67c(1.7g)。Dissolve 67A (2.95g, 10.68mmol) in 50mL DMSO, add the hydrochloride (1.7g) of the crude product 67b, add DIPEA (4.14g, 32.03mmol), and react at 80°C for 3 hours. The reaction system was cooled to room temperature, slowly poured into 400 mL of water, filtered, the filter cake was washed with 20 mL of water, and the filter cake was dried under reduced pressure to obtain crude product 67c (1.7 g).
第二步：化合物67的制备Step 2: Preparation of Compound 67
将上述粗品67c(0.2g)、2c(0.32g，0.68mmol)和TEA(0.17g，1.68mmol)加入到5mL DMF中，置换氮气三次，加入CuI(11mg，0.058mmol)和PdCl2(PPh3)2(40mg，0.057mmol)，氮气氛围下50℃反应1.5h。将反应液冷却至室温，加入60mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:2)，得到化合物67(110mg，收率：23％)。Add the above crude products 67c (0.2g), 2c (0.32g, 0.68mmol) and TEA (0.17g, 1.68mmol) to 5mL DMF, replace nitrogen three times, add CuI (11mg, 0.058mmol) and PdCl 2 (PPh 3 ) 2 (40mg, 0.057mmol), reacted at 50℃ for 1.5h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 60 mL of water, and perform suction filtration. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/petroleum ether/ Ethyl acetate (v/v)=1:2) to obtain compound 67 (110 mg, yield: 23%).
1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.54(d,1H),8.02(s,1H),7.71(s,1H),7.64(d,1H),7.61–7.55(m,2H),7.50(dd,1H),6.79(d,1H),6.52(dd,1H),4.97–4.89(m,1H),4.24–4.12(m,2H),3.89–3.80(m,2H),3.12–2.98(m,3H),2.94–2.65(m,7H),2.28–1.98(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.68(s,1H),8.54(d,1H),8.02(s,1H),7.71(s,1H),7.64(d,1H),7.61–7.55( m,2H),7.50(dd,1H),6.79(d,1H),6.52(dd,1H),4.97–4.89(m,1H),4.24–4.12(m,2H),3.89–3.80(m, 2H),3.12–2.98(m,3H),2.94–2.65(m,7H),2.28–1.98(m,3H).
实施例68：化合物68的制备
Example 68: Preparation of Compound 68
第一步：68c的制备Step One: Preparation of 68c
向反应瓶中分别加入1-氯-N,N,2-三甲基丙烯胺(0.72g,5.38mmol)、2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸(1.00g，3.58mmol)和DCM(20mL)，室温搅拌1h后，依次加入TEA(1.48mL,10.65mmol)和68b(0.56g,3.54mmol)，室温反应1h。将反应液减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:5)，得68c(1.05g，收率：71％)。Add 1-chloro-N,N,2-trimethylpropenylamine (0.72g, 5.38mmol) and 2-(4-iodo-1H-pyrazol-1-yl)-2-methyl to the reaction bottle respectively. Propionic acid (1.00g, 3.58mmol) and DCM (20mL) were stirred at room temperature for 1 h, then TEA (1.48mL, 10.65mmol) and 68b (0.56g, 3.54mmol) were added in sequence, and the reaction was carried out at room temperature for 1h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:5) to obtain 68c (1.05 g, yield: 71%).
LCMS m/z＝421.0[M+1]+。LCMS m/z=421.0[M+1] + .
以化合物68c+67c为原料，参考实施例67得到化合物68(130mg)。 Using compounds 68c+67c as raw materials, compound 68 (130 mg) was obtained with reference to Example 67.
1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.36(d,1H),8.02(s,1H),7.71–7.60(m,3H),7.48(dd,1H),7.40–7.33(m,1H),6.82–6.76(m,1H),6.56–6.48(m,1H),4.98–4.88(m,1H),4.24–4.12(m,2H),3.90–3.79(m,2H),3.14–3.00(m,1H),2.95–2.65(m,5H),2.17–2.07(m,1H),1.93(s,6H),1.53–1.42(m,1H),1.00–0.90(m,2H),0.61–0.51(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.05(s,1H),8.36(d,1H),8.02(s,1H),7.71–7.60(m,3H),7.48(dd,1H),7.40– 7.33(m,1H),6.82–6.76(m,1H),6.56–6.48(m,1H),4.98–4.88(m,1H),4.24–4.12(m,2H),3.90–3.79(m,2H ),3.14–3.00(m,1H),2.95–2.65(m,5H),2.17–2.07(m,1H),1.93(s,6H),1.53–1.42(m,1H),1.00–0.90(m ,2H),0.61–0.51(m,2H).
实施例69：化合物69的制备
Example 69: Preparation of Compound 69
以化合物69a为原料，参考实施例22得到化合物69(0.20g)。Using compound 69a as a raw material, compound 69 (0.20 g) was obtained with reference to Example 22.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.94(s,1H),7.76(s,1H),7.72–7.62(m,2H),7.44–7.37(m,2H),7.32–7.23(m,2H),7.08(t,1H),6.80(s,1H),6.58–6.52(m,1H),4.93(dd,1H),4.40–4.30(m,2H),4.12–4.01(m,2H),3.87–3.74(m,1H),3.14–2.97(m,2H),2.95–2.64(m,5H),2.27–1.96(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.12(s,1H),7.94(s,1H),7.76(s,1H),7.72–7.62(m,2H),7.44–7.37(m,2H), 7.32–7.23(m,2H),7.08(t,1H),6.80(s,1H),6.58–6.52(m,1H),4.93(dd,1H),4.40–4.30(m,2H),4.12– 4.01(m,2H),3.87–3.74(m,1H),3.14–2.97(m,2H),2.95–2.64(m,5H),2.27–1.96(m,3H).
LCMS m/z＝577.2[M+1]+ LCMS m/z＝577.2[M+1] +
实施例70：化合物70的制备
Example 70: Preparation of Compound 70
第一步：70b的制备Step One: Preparation of 70b
将2c(1.0g，2.13mmol)、70a(1.30g，10.63mmol)(合成方法见WO2018052949)和三乙胺(1.05g，10.38mmol)溶于20mL DCM中，置换氮气三次，加入CuI(40.6mg，0.213mmol)和PdCl2(PPh3)2(150mg，0.214mmol)，氮气氛围下室温反应16h。将反应液减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到70b(0.3g，收率：30％)。Dissolve 2c (1.0g, 2.13mmol), 70a (1.30g, 10.63mmol) (see WO2018052949 for synthesis method) and triethylamine (1.05g, 10.38mmol) in 20mL DCM, replace nitrogen three times, and add CuI (40.6mg , 0.213mmol) and PdCl 2 (PPh 3 ) 2 (150mg, 0.214mmol), reacted at room temperature for 16h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain 70b (0.3 g, yield: 30%).
第二步：70c的制备Step 2: Preparation of 70c
将70b(0.15g，0.32mmol)溶于5mL THF中，加入四丁基氟化铵三水合物(0.20g，0.63mmol)，室温反应0.5h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得70c(0.12g，收率：96％)。Dissolve 70b (0.15g, 0.32mmol) in 5mL THF, add tetrabutylammonium fluoride trihydrate (0.20g, 0.63mmol), and react at room temperature for 0.5h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 70c (0.12g, yield: 96%).
第三步：化合物70的制备Step 3: Preparation of Compound 70
将70c(0.12g，0.31mmol)、70A(0.16g，0.47mmol)和TEA(0.10g，0.99mmol)加入到5mL DMF中，置换氮气三次，加入CuI(6mg，0.032mmol)和PdCl2(PPh3)2(22mg，0.031mmol)，置换氮气三次，50℃反应1.5h。将反应液冷却至室温，加入60mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石 油醚/乙酸乙酯(v/v)＝1:2)，得到化合物70(30mg，收率：15％)。Add 70c (0.12g, 0.31mmol), 70A (0.16g, 0.47mmol) and TEA (0.10g, 0.99mmol) to 5mL DMF, replace nitrogen three times, add CuI (6mg, 0.032mmol) and PdCl 2 (PPh 3 ) 2 (22 mg, 0.031 mmol), replace nitrogen three times, and react at 50°C for 1.5 hours. Cool the reaction solution to room temperature, add 60 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (Stone Oil ether/ethyl acetate (v/v)=1:2) to obtain compound 70 (30 mg, yield: 15%).
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.55(d,1H),8.02–7.80(m,6H),7.64–7.57(m,1H),7.56–7.48(m,1H),5.04–4.92(m,1H),3.18–3.03(m,2H),2.99–2.67(m,5H),2.34–1.99(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.71(s,1H),8.55(d,1H),8.02–7.80(m,6H),7.64–7.57(m,1H),7.56–7.48(m,1H ),5.04–4.92(m,1H),3.18–3.03(m,2H),2.99–2.67(m,5H),2.34–1.99(m,3H).
实施例71：化合物71的制备
Example 71: Preparation of Compound 71
第一步：71b的制备Step One: Preparation of 71b
将71a(5.0g，20.49mmol)溶于80mL THF中，氮气氛围下冷却至0℃，缓慢分批加入60％氢化钠(1.23g)，室温搅拌1h后，加入SEMCl(5.12g，30.71mmol)，室温反应16h。加入200mL饱和氯化铵水溶液，用200mL DCM萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚)，得到71b(7.0g，收率：91％)。Dissolve 71a (5.0g, 20.49mmol) in 80mL THF, cool to 0°C under nitrogen atmosphere, slowly add 60% sodium hydride (1.23g) in batches, stir at room temperature for 1 hour, then add SEMCl (5.12g, 30.71mmol) , react at room temperature for 16h. Add 200 mL saturated aqueous ammonium chloride solution, extract with 200 mL DCM, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether) to obtain 71b (7.0 g, yield :91%).
LCMS m/z＝375.3[M+1]+ LCMS m/z＝375.3[M+1] +
第二步：71c的制备Step 2: Preparation of 71c
将71b(7.0g，18.7mmol)溶于80mL DMSO中，加入3-乙炔基氮杂环丁烷盐酸盐(5.02g，42.69mmol)和碳酸钾(8.86g，64.11mmol)，置换氮气三次，加入CuI(0.81g，4.25mmol)和L-脯氨酸(0.98g，8.51mmol)，置换氮气三次，100℃反应16h。将反应体系冷却至室温，加入到60mL水中，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)，得71c(3.7g，收率：60％)。Dissolve 71b (7.0g, 18.7mmol) in 80mL DMSO, add 3-ethynyl azetidine hydrochloride (5.02g, 42.69mmol) and potassium carbonate (8.86g, 64.11mmol), replace nitrogen three times, Add CuI (0.81g, 4.25mmol) and L-proline (0.98g, 8.51mmol), replace nitrogen three times, and react at 100°C for 16 hours. The reaction system was cooled to room temperature, added to 60 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate). (v/v)=10:1), 71c (3.7g, yield: 60%) was obtained.
LCMS m/z＝328.2[M+1]+ LCMS m/z＝328.2[M+1] +
第三步：71d的制备Step 3: Preparation of 71d
将71c(1.5g，4.58mmol)溶于20mL THF中，加入四丁基氟化铵三水合物(14.45g，45.81mmol)，70℃反应16h。将反应液冷却至室温，加入50mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝15:1)，得到71d(800mg，收率：89％)。Dissolve 71c (1.5g, 4.58mmol) in 20mL THF, add tetrabutylammonium fluoride trihydrate (14.45g, 45.81mmol), and react at 70°C for 16h. The reaction solution was cooled to room temperature, 50 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v /v)=15:1), 71d (800 mg, yield: 89%) was obtained.
LCMS m/z＝198.3[M+1]+ LCMS m/z＝198.3[M+1] +
第四步：71e-1和71e-2的制备Step 4: Preparation of 71e-1 and 71e-2
将71d(0.8g，4.05mmol)溶于20mL DMF中，氮气氛围下冷却至0℃，缓慢分批加入60％氢化钠(0.32g)，室温搅拌1h后，加入3-溴哌啶-2,6-二酮(1.00g，5.21mmol)，室温反应16h。向反应体系中加入200mL饱和氯化铵水溶液，用200mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，所 得粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05mol/L乙酸铵)。梯度洗脱方法：乙腈由10％梯度洗脱60％(洗脱时间15min)，冻干得到分别得到71e-1(0.14g，收率：11％)和71e-2(0.18g，收率：14％)。Dissolve 71d (0.8g, 4.05mmol) in 20mL DMF, cool to 0°C under nitrogen atmosphere, slowly add 60% sodium hydride (0.32g) in batches, stir at room temperature for 1 hour, then add 3-bromopiperidine-2, 6-diketone (1.00g, 5.21mmol), reacted at room temperature for 16h. Add 200 mL saturated aqueous ammonium chloride solution to the reaction system, extract with 200 mL ethyl acetate, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/methanol ( v/v)=15:1), so The crude product was passed through Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05mol/L ammonium acetate). Gradient elution method: acetonitrile was eluted from 10% gradient to 60% (elution time 15 minutes), and then lyophilized to obtain 71e-1 (0.14g, yield: 11%) and 71e-2 (0.18g, yield: 11%). 14%).
71e-1的洗脱时间：13min；Elution time of 71e-1: 13min;
71e-2的洗脱时间：14min。Elution time of 71e-2: 14min.
第五步：化合物71的制备Step 5: Preparation of Compound 71
将71e-1(0.07g，0.23mmol)、2c(0.13g，0.28mmol)和TEA(0.07g，0.69mmol)加入到5mL DMF中，置换氮气三次，加入CuI(5mg，0.026mmol)和PdCl2(PPh3)2(16mg，0.023mmol)，氮气氛围下50℃反应1.5h。将反应液冷却至室温，加入60mL水，抽滤，滤饼用10mL水洗涤，将滤饼用50mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:2)，得到化合物71(35mg，收率：23.41％)。Add 71e-1 (0.07g, 0.23mmol), 2c (0.13g, 0.28mmol) and TEA (0.07g, 0.69mmol) to 5mL DMF, replace nitrogen three times, add CuI (5mg, 0.026mmol) and PdCl 2 (PPh 3 ) 2 (16 mg, 0.023 mmol), reacted at 50°C for 1.5 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 60 mL of water, and suction filter. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 50 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/petroleum ether/ Ethyl acetate (v/v)=1:2) to obtain compound 71 (35 mg, yield: 23.41%).
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.54(d,1H),8.00(s,1H),7.83(s,1H),7.77(s,1H),7.68(s,1H),7.63–7.55(m,2H),7.53–7.47(m,1H),6.83–6.70(m,1H),6.51(s,1H),5.29–5.18(m,1H),4.29–4.17(m,2H),3.94–3.83(m,2H),3.79–3.65(m,1H),3.14–3.00(m,3H),2.94–2.70(m,4H),2.60–2.47(m,1H),2.30–2.15(m,1H),2.15–2.02(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.69(s,1H),8.54(d,1H),8.00(s,1H),7.83(s,1H),7.77(s,1H),7.68(s, 1H),7.63–7.55(m,2H),7.53–7.47(m,1H),6.83–6.70(m,1H),6.51(s,1H),5.29–5.18(m,1H),4.29–4.17( m,2H),3.94–3.83(m,2H),3.79–3.65(m,1H),3.14–3.00(m,3H),2.94–2.70(m,4H),2.60–2.47(m,1H), 2.30–2.15(m,1H),2.15–2.02(m,1H).
实施例72：化合物72的制备
Example 72: Preparation of Compound 72
以化合物71e-2为原料，参考实施例71得到化合物72(85mg)。Using compound 71e-2 as a raw material, compound 72 (85 mg) was obtained with reference to Example 71.
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.54(d,1H),8.10(s,1H),7.91(s,1H),7.77(s,1H),7.68(s,1H),7.60–7.55(m,1H),7.53–7.46(m,1H),7.29–7.23(m,1H),6.79–6.67(m,2H),5.32–5.22(m,1H),4.30–4.18(m,2H),3.93–3.82(m,2H),3.80–3.67(m,1H),3.14–2.98(m,3H),2.91–2.67(m,4H),2.52–2.38(m,1H),2.30–2.01(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.69(s,1H),8.54(d,1H),8.10(s,1H),7.91(s,1H),7.77(s,1H),7.68(s, 1H),7.60–7.55(m,1H),7.53–7.46(m,1H),7.29–7.23(m,1H),6.79–6.67(m,2H),5.32–5.22(m,1H),4.30– 4.18(m,2H),3.93–3.82(m,2H),3.80–3.67(m,1H),3.14–2.98(m,3H),2.91–2.67(m,4H),2.52–2.38(m,1H ),2.30–2.01(m,2H).
实施例73：化合物73的制备
Example 73: Preparation of Compound 73
第一步：73b的合成Step One: Synthesis of 73b
将73a(375mg,2.00mmol)溶于10mL二氯甲烷中，加入73A(0.59g，2.43mmol)和TCFH(0.85g,3.03mmol)，加入NMI(0.66g,8.04mmol)，室温反应16h。将反应体系减压浓缩，加入50mL饱和碳酸氢钠水溶液，用100mL二氯甲烷萃取，有机相用25mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝5:1)，得到73b(800mg， 收率：97％)。Dissolve 73a (375 mg, 2.00 mmol) in 10 mL dichloromethane, add 73A (0.59 g, 2.43 mmol) and TCFH (0.85 g, 3.03 mmol), add NMI (0.66 g, 8.04 mmol), and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 50 mL of saturated sodium bicarbonate aqueous solution was added, extracted with 100 mL of methylene chloride, the organic phase was washed with 25 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (petroleum ether: Ethyl acetate (v/v)=5:1) to obtain 73b (800 mg, Yield: 97%).
LCMS m/z＝412.0[M+1]+ LCMS m/z＝412.0[M+1] +
以化合物73b为原料，参考实施例45得到化合物73(50mg)。Using compound 73b as a raw material, compound 73 (50 mg) was obtained with reference to Example 45.
1H NMR(400MHz,CDCl3)δ8.39(d,1H),8.09(s,1H),7.67(d,1H),7.52–7.38(m,3H),7.34(s,1H),7.30–7.21(m,2H),6.85–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H),3.92–3.77(m,1H),3.48–3.36(m,2H),2.95–2.65(m,5H),2.18–2.05(m,1H),1.63(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.39(d,1H),8.09(s,1H),7.67(d,1H),7.52–7.38(m,3H),7.34(s,1H),7.30– 7.21(m,2H),6.85–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H), 3.92–3.77(m,1H),3.48–3.36(m,2H),2.95–2.65(m,5H),2.18–2.05(m,1H),1.63(s,6H).
实施例74：化合物74的制备
Example 74: Preparation of Compound 74
以化合物74a为原料，参考实施例44得到化合物74(0.065g)。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.50(s,1H),8.07–7.97(m,3H),7.89–7.75(m,3H),7.69(d,1H),6.89(d,1H),6.74(dd,1H),5.12–5.02(m,1H),4.49–4.37(m,2H),4.17–4.06(m,2H),4.04–3.92(m,1H),2.98–2.81(m,1H),2.65–2.45(m,2H),2.08–1.96(m,1H).Using compound 74a as a raw material, compound 74 (0.065g) was obtained with reference to Example 44. 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),10.50(s,1H),8.07–7.97(m,3H),7.89–7.75(m,3H),7.69(d,1H ),6.89(d,1H),6.74(dd,1H),5.12–5.02(m,1H),4.49–4.37(m,2H),4.17–4.06(m,2H),4.04–3.92(m,1H ),2.98–2.81(m,1H),2.65–2.45(m,2H),2.08–1.96(m,1H).
实施例75：化合物75的制备
Example 75: Preparation of Compound 75
以化合物75a为原料，参考实施例44得到化合物75(0.06g)。Using compound 75a as a raw material, compound 75 (0.06g) was obtained with reference to Example 44.
1H NMR(400MHz,CDCl3)δ8.70(d,1H),8.45(s,1H),7.95–7.86(m,1H),7.77–7.55(m,4H),7.52–7.31(m,2H),6.88–6.80(m,1H),6.64–6.53(m,1H),4.99–4.89(m,1H),4.48–4.33(m,2H),4.20–4.06(m,2H),3.95–3.81(m,1H),2.97–2.65(m,3H),2.18–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.70(d,1H),8.45(s,1H),7.95–7.86(m,1H),7.77–7.55(m,4H),7.52–7.31(m,2H ),6.88–6.80(m,1H),6.64–6.53(m,1H),4.99–4.89(m,1H),4.48–4.33(m,2H),4.20–4.06(m,2H),3.95–3.81 (m,1H),2.97–2.65(m,3H),2.18–2.07(m,1H).
实施例76：化合物76的制备
Example 76: Preparation of Compound 76
以化合物76c为原料，参考实施例19得到化合物76(10mg)。Using compound 76c as a raw material, compound 76 (10 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.32(d,1H),7.99(s,1H),7.82–7.76(m,2H),7.67(d,1H),7.29–7.23(m,1H),7.21–7.13(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.28(q,2H),2.95–2.65(m,3H),2.18–2.07(m,1H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.87(s,1H),8.32(d,1H),7.99(s,1H),7.82–7.76(m,2H),7.67(d,1H),7.29– 7.23(m,1H),7.21–7.13(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H), 4.13–4.00(m,2H),3.88–3.75(m,1H),3.28(q,2H),2.95–2.65(m,3H),2.18–2.07(m,1H),1.94(s,6H).
实施例77：化合物77的制备
Example 77: Preparation of Compound 77
以化合物71e-2为原料，参考实施例71得到化合物77(80mg)。Using compound 71e-2 as a raw material, compound 77 (80 mg) was obtained with reference to Example 71.
1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.37(d,1H),8.02(s,1H),7.91(s,1H),7.78(s,1H),7.70(s,1H),7.48(dd,1H),7.39–7.34(m,1H),7.31–7.24(m,1H),6.81–6.67(m,2H),5.33–5.22(m,1H),4.30–4.18(m,2H),3.94–3.83(m,2H),2.99–3.67(m,1H),3.13–3.00(m,1H),2.92–2.72(m,2H),2.53–2.40(m,1H),1.95(s,6H),1.55–1.42(m,1H),1.04–0.92(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.07(s,1H),8.37(d,1H),8.02(s,1H),7.91(s,1H),7.78(s,1H),7.70(s, 1H),7.48(dd,1H),7.39–7.34(m,1H),7.31–7.24(m,1H),6.81–6.67(m,2H),5.33–5.22(m,1H),4.30–4.18( m,2H),3.94–3.83(m,2H),2.99–3.67(m,1H),3.13–3.00(m,1H),2.92–2.72(m,2H),2.53–2.40(m,1H), 1.95(s,6H),1.55–1.42(m,1H),1.04–0.92(m,2H),0.60–0.52(m,2H).
实施例78：化合物78的制备
Example 78: Preparation of Compound 78
以化合物71e-1为原料，参考实施例71得到化合物78(40mg)。Using compound 71e-1 as a starting material, compound 78 (40 mg) was obtained with reference to Example 71.
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.37(d,1H),8.16(s,1H),7.82(s,1H),7.78(s,1H),7.70(s,1H),7.60(d,1H),7.48(dd,1H),7.40–7.33(m,1H),6.75(dd,1H),6.47(s,1H),5.28–5.19(m,1H),4.28–4.17(m,2H),3.93–3.81(m,2H),3.77–3.64(m,1H),3.14–3.01(m,1H),2.94–2.70(m,2H),2.59–2.47(m,1H),1.95(s,6H),1.55–1.43(m,1H),1.02–0.92(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.06(s,1H),8.37(d,1H),8.16(s,1H),7.82(s,1H),7.78(s,1H),7.70(s, 1H),7.60(d,1H),7.48(dd,1H),7.40–7.33(m,1H),6.75(dd,1H),6.47(s,1H),5.28–5.19(m,1H),4.28 –4.17(m,2H),3.93–3.81(m,2H),3.77–3.64(m,1H),3.14–3.01(m,1H),2.94–2.70(m,2H),2.59–2.47(m, 1H),1.95(s,6H),1.55–1.43(m,1H),1.02–0.92(m,2H),0.60–0.52(m,2H).
实施例79：化合物79的制备
Example 79: Preparation of Compound 79
以化合物79b为原料，参考实施例19得到化合物79(380mg)。Using compound 79b as a raw material, compound 79 (380 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.15(s,1H),7.87(d,1H),7.78(s,1H),7.74(s,1H),7.67(d,1H),7.30–7.23(m,1H),7.19(dd,1H),6.83–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.02(m,2H),3.89–3.74(m,1H),2.94–2.65(m,3H),2.19–2.06(m,1H),1.98–1.82(m,7H),1.04–0.92(m,2H),0.72–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.49(s,1H),8.15(s,1H),7.87(d,1H),7.78(s,1H),7.74(s,1H),7.67(d, 1H),7.30–7.23(m,1H),7.19(dd,1H),6.83–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m, 2H),4.14–4.02(m,2H),3.89–3.74(m,1H),2.94–2.65(m,3H),2.19–2.06(m,1H),1.98–1.82(m,7H),1.04– 0.92(m,2H),0.72–0.62(m,2H).
LCMS m/z＝673.2[M+1]+ LCMS m/z＝673.2[M+1] +
实施例80：化合物80的制备
Example 80: Preparation of Compound 80
以化合物80b为原料，参考实施例19得到化合物80(150mg)。Using compound 80b as a raw material, compound 80 (150 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.13(d,1H),8.04(s,1H),7.82–7.74(m,2H),7.67(d,1H),7.04–6.99(m,1H),6.94(dd,1H),6.81(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30 (m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.64(m,3H),2.20–2.06(m,1H),1.94(s,6H),1.87–1.75(m,1H),0.98–0.87(m,2H),0.67–0.57(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.63(s,1H),8.13(d,1H),8.04(s,1H),7.82–7.74(m,2H),7.67(d,1H),7.04– 6.99(m,1H),6.94(dd,1H),6.81(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30 (m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.64(m,3H),2.20–2.06(m,1H),1.94(s,6H),1.87 –1.75(m,1H),0.98–0.87(m,2H),0.67–0.57(m,2H).
LCMS m/z＝639.2[M+1]+ LCMS m/z＝639.2[M+1] +
实施例81：化合物81的制备
Example 81: Preparation of Compound 81
第一步：81b的制备Step One: Preparation of 81b
在氮气保护下将60％氢化钠(3.4g)加入到60mL DMF中，冷却至0℃，缓慢滴加丙二酸二乙酯(6.8g，42.45mmol)，0℃反应30min后，室温反应30min。0℃下缓慢滴加81a(6.0g，28.7mmol)，室温反应3h。0℃下向反应体系中加入10mL水，用乙酸乙酯萃取(80mL×3)，有机相用饱和氯化钠水溶液洗涤(60mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝10:1)，得粗品81b(10.5g)。Add 60% sodium hydride (3.4g) to 60mL DMF under nitrogen protection, cool to 0°C, slowly add diethyl malonate (6.8g, 42.45mmol) dropwise, react at 0°C for 30 minutes, then react at room temperature for 30 minutes . 81a (6.0g, 28.7mmol) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 3 hours. Add 10 mL of water to the reaction system at 0°C, extract with ethyl acetate (80 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (60 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is washed with silica gel Chromatographic column separation and purification (petroleum ether:ethyl acetate (v/v)=10:1) gave crude product 81b (10.5g).
第二步：81c的制备Step 2: Preparation of 81c
将上述粗品81b(10.5g)溶于60mL冰乙酸和30mL浓盐酸的混合溶剂中，100℃反应16h。将反应体系冷却至室温，加入水(400mL)，用乙酸乙酯萃取(90mL×2)，有机相用饱和氯化钠水溶液洗涤(20ml×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝4:1)，得粗品(5.2g)。将上述粗品(5.2g)溶于80mL甲醇中，0℃下缓慢滴加二氯亚砜(3ml)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝10:1)，得81c(3.3g，从化合物81a算两步收率：44％)。The above crude product 81b (10.5g) was dissolved in a mixed solvent of 60mL glacial acetic acid and 30mL concentrated hydrochloric acid, and reacted at 100°C for 16h. Cool the reaction system to room temperature, add water (400mL), extract with ethyl acetate (90mL×2), wash the organic phase with saturated aqueous sodium chloride solution (20ml×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product Separate and purify using silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=4:1) to obtain crude product (5.2g). Dissolve the above crude product (5.2g) in 80mL methanol, slowly add thionyl chloride (3ml) dropwise at 0°C, and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain 81c (3.3g, two-step yield calculated from compound 81a: 44%) .
LCMS m/z＝264.1[M+1]+ LCMS m/z＝264.1[M+1] +
第三步：81d的制备Step 3: Preparation of 81d
在氮气保护下将81c(3.3g，12.5mmol)溶于40mL DMF中，0℃下缓慢分批加入60％氢化钠(2.0g)，0℃反应30min后，室温反应1h，0℃下缓慢加入碘甲烷(6.1g，42.98mmol)，室温反应3h。向反应体系中加入水(150mL)，用乙酸乙酯萃取(60mL×2)，有机相用饱和氯化钠水溶液洗涤(80mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝10:1)，得81d(2.6g，收率：71％)。Dissolve 81c (3.3g, 12.5mmol) in 40mL DMF under nitrogen protection, slowly add 60% sodium hydride (2.0g) in batches at 0℃, react at 0℃ for 30min, react at room temperature for 1h, and slowly add at 0℃ Methyl iodide (6.1g, 42.98mmol), reacted at room temperature for 3h. Add water (150mL) to the reaction system, extract with ethyl acetate (60mL×2), wash the organic phase with saturated aqueous sodium chloride solution (80mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is chromatographed on silica gel Column separation and purification (petroleum ether: ethyl acetate (v/v) = 10:1) gave 81d (2.6 g, yield: 71%).
LCMS m/z＝292.1[M+1]+ LCMS m/z＝292.1[M+1] +
第四步：81e的制备Step 4: Preparation of 81e
将81d(2.6g，8.93mmol)加入到250mL单口瓶中，依次加入乙醇(50mL)、水(10mL)、氯化铵(2.4g，44.9mmol)和还原铁粉(2.5g，44.64mmol)，70℃反应4h。将反应体系冷却至室温，垫硅藻土过滤，向滤液中加入水(200mL)，用乙酸乙酯萃取(80mL×2)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝73:27)，得81e(2.2g，收率：94％)。 Add 81d (2.6g, 8.93mmol) into a 250mL single-mouth bottle, then add ethanol (50mL), water (10mL), ammonium chloride (2.4g, 44.9mmol) and reduced iron powder (2.5g, 44.64mmol), React at 70°C for 4 hours. Cool the reaction system to room temperature, filter through diatomaceous earth, add water (200mL) to the filtrate, extract with ethyl acetate (80mL×2), wash the organic phase with saturated sodium chloride aqueous solution (60mL×2), anhydrous Dry over sodium sulfate and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=73:27) to obtain 81e (2.2g, yield: 94%).
LCMS m/z＝262.1[M+1]+ LCMS m/z＝262.1[M+1] +
第五步：81f的制备Step 5: Preparation of 81f
将81e(1.2g，4.59mmol)溶于甲苯(10mL)和水(10mL)中，0℃加入浓盐酸(3mL)，搅拌10min后缓慢加入亚硝酸钠(380mg，5.51mmol)，0-5℃反应30min，加入10mL碘化钾(1.5g，9.04mmol)的水溶液，室温反应2h。向反应体系中加入水(50mL)，用乙酸乙酯萃取(40mL×2)，有机相用饱和硫代硫酸钠溶液洗涤(40mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝92:8)，得81f(1.5g，收率：88％)。Dissolve 81e (1.2g, 4.59mmol) in toluene (10mL) and water (10mL), add concentrated hydrochloric acid (3mL) at 0℃, stir for 10min, then slowly add sodium nitrite (380mg, 5.51mmol), 0-5℃ React for 30 minutes, add 10 mL of potassium iodide (1.5 g, 9.04 mmol) aqueous solution, and react at room temperature for 2 hours. Add water (50mL) to the reaction system, extract with ethyl acetate (40mL×2), wash the organic phase with saturated sodium thiosulfate solution (40mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is washed with silica gel Chromatographic column separation and purification (petroleum ether:ethyl acetate (v/v)=92:8) gave 81f (1.5g, yield: 88%).
LCMS m/z＝373.1[M+1]+ LCMS m/z＝373.1[M+1] +
第六步：81g的制备Step 6: Preparation of 81g
将81f(1.5g，4.03mmol)加入到100mL单口瓶中，依次加入四氢呋喃(60mL)、水(6mL)和一水合氢氧化锂(850mg，20.26mmol)，室温反应16h。将反应体系用0.5mol/L盐酸调pH至5，用乙酸乙酯萃取(30mL×2)，有机相用饱和氯化钠水溶液洗涤(40mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝72:28)，得粗品(1.1g)。将上述粗品(0.1g)溶于10mL二氯甲烷中，加入66b(45mg，0.28mmol)、TCFH(118mg，0.42mmol)、N-甲基咪唑(92mg，1.12mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝84:16)，得81g(90mg，收率：65％)。Add 81f (1.5g, 4.03mmol) into a 100mL single-neck bottle, add tetrahydrofuran (60mL), water (6mL) and lithium hydroxide monohydrate (850mg, 20.26mmol) in sequence, and react at room temperature for 16h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (30 mL × 2), wash the organic phase with saturated sodium chloride aqueous solution (40 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=72:28) to obtain the crude product (1.1g). Dissolve the above crude product (0.1g) in 10 mL of dichloromethane, add 66b (45 mg, 0.28 mmol), TCFH (118 mg, 0.42 mmol), and N-methylimidazole (92 mg, 1.12 mmol), and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 84:16) to obtain 81 g (90 mg, yield: 65%).
LCMS m/z＝499.1[M+1]+ LCMS m/z＝499.1[M+1] +
第七步：化合物81的制备Step 7: Preparation of Compound 81
将81g(90mg，0.18mmol)加入到50mL单口瓶中，依次加入干燥DMF(12mL)、上述粗品中间体1(91mg)和TEA(54mg，0.53mmol)，置换氮气三次，加入PdCl2(PPh3)2(13mg，0.019mmol)和CuI(6mg，0.032mmol)，置换氮气三次，60℃反应2h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(150mL)，用乙酸乙酯萃取(30mL×2)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝23:77)，得化合物81(60mg，收率：47％)。Add 81g (90mg, 0.18mmol) into a 50mL single-mouth bottle, add dry DMF (12mL), the above crude intermediate 1 (91mg) and TEA (54mg, 0.53mmol) in sequence, replace nitrogen three times, and add PdCl 2 (PPh 3 ) 2 (13 mg, 0.019 mmol) and CuI (6 mg, 0.032 mmol), replaced with nitrogen three times, and reacted at 60°C for 2 hours. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (150mL), extract with ethyl acetate (30mL×2), wash the organic phase with saturated aqueous sodium chloride solution (30mL×2), and dry over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 23:77) to obtain compound 81 (60 mg, yield: 47%).
1H NMR(400MHz,CDCl3)δ8.43(d,1H),7.93(s,1H),7.78–7.66(m,3H),7.63–7.56(m,2H),7.56–7.48(m,1H),7.41–7.35(m,1H),6.86–6.80(m,1H),6.58(dd,1H),4.98–4.89(m,1H),4,47–4.35(m,2H),4.18–4.06(m,2H),3.97–3.84(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.73(s,6H),1.28–1.17(m,1H),0.62–0.53(m,2H),0.40–0.32(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.43(d,1H),7.93(s,1H),7.78–7.66(m,3H),7.63–7.56(m,2H),7.56–7.48(m,1H ),7.41–7.35(m,1H),6.86–6.80(m,1H),6.58(dd,1H),4.98–4.89(m,1H),4,47–4.35(m,2H),4.18–4.06 (m,2H),3.97–3.84(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.73(s,6H),1.28–1.17(m,1H),0.62 –0.53(m,2H),0.40–0.32(m,2H).
LCMS m/z＝706.8[M-1]- LCMS m/z＝706.8[M-1] -
实施例82：化合物82的制备
Example 82: Preparation of Compound 82
LCMS m/z＝271.1[M+1]+ LCMS m/z＝271.1[M+1] +
第一步：82c的制备Step One: Preparation of 82c
将82b(0.3g，1.11mmol)溶于15mL乙腈中，依次加入28B(390mg，1.094mmol)和碳酸铯(715mg，2.19mmol)，90℃反应16h。将反应体系冷却至室温，加入150mL水，用乙酸乙酯萃取(50mL×2)，有机相用饱和氯化钠水溶液洗涤(20mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝80:20)，得82c(50mg，收率：8％)。Dissolve 82b (0.3g, 1.11mmol) in 15mL acetonitrile, add 28B (390mg, 1.094mmol) and cesium carbonate (715mg, 2.19mmol) in sequence, and react at 90°C for 16h. Cool the reaction system to room temperature, add 150 mL of water, extract with ethyl acetate (50 mL × 2), wash the organic phase with saturated aqueous sodium chloride solution (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is washed with silica gel Chromatographic column separation and purification (petroleum ether: ethyl acetate (v/v) = 80:20) gave 82c (50 mg, yield: 8%).
LCMS m/z＝546.1[M+1]+ LCMS m/z＝546.1[M+1] +
以82c和中间体1为原料，参考化合物81第七步的制备方法得化合物82(35mg)。Using 82c and intermediate 1 as raw materials, compound 82 (35 mg) was obtained by referring to the preparation method of the seventh step of compound 81.
1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.59–8.52(m,1H),8.17–8.09(m,2H),7.93(s,1H),7.79(s,1H),7.73–7.65(m,1H),7.54–7.34(m,5H),6.84–6.79(m,1H),6.56(dd,1H),4.99–4.89(m,1H),4.43–4.32(m,2H),4.14–4.04(m,2H),3.94–3.81(m,1H),3.17–3.03(m,2H),2.95–2.63(m,5H),2.32–2.05(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.02(s,1H),8.59–8.52(m,1H),8.17–8.09(m,2H),7.93(s,1H),7.79(s,1H), 7.73–7.65(m,1H),7.54–7.34(m,5H),6.84–6.79(m,1H),6.56(dd,1H),4.99–4.89(m,1H),4.43–4.32(m,2H ),4.14–4.04(m,2H),3.94–3.81(m,1H),3.17–3.03(m,2H),2.95–2.63(m,5H),2.32–2.05(m,3H).
实施例83和84：化合物83与化合物84的制备
Examples 83 and 84: Preparation of Compound 83 and Compound 84
第一步：83a的制备Step 1: Preparation of 83a
向反应瓶中分别加入2-溴-2-甲基丙酸(1.5g,8.98mmol)与10mL二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺(1.80g,13.47mmol)，室温搅拌1h后，加入TEA(2.72g,26.88mmol)与16B(1.70g,10.75mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20)，得到83a(1.46g,产率：53％)。Add 2-bromo-2-methylpropionic acid (1.5g, 8.98mmol) and 10mL dichloromethane to the reaction bottle respectively, and add 1-chloro-N,N,2-trimethylpropenylamine (1.80g, 13.47 mmol), stirred at room temperature for 1 h, then added TEA (2.72g, 26.88mmol) and 16B (1.70g, 10.75mmol), and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 83a (1.46 g, yield: 53%).
第二步：83b-1与83b-2的制备Step 2: Preparation of 83b-1 and 83b-2
向反应瓶中分别加入3-碘-1H-吡唑(1.0g,5.16mmol)、83a(1.91g,6.22mmol)、碳酸铯(3.37g,10.34mmol)和15mL乙腈，50℃反应4h。将反应体系冷却至室温，过滤，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20)，得到粗品83b-1与83b-2的混合物(1.0g)。Add 3-iodo-1H-pyrazole (1.0g, 5.16mmol), 83a (1.91g, 6.22mmol), cesium carbonate (3.37g, 10.34mmol) and 15mL acetonitrile to the reaction bottle, and react at 50°C for 4 hours. The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain a mixture of crude products 83b-1 and 83b-2 ( 1.0g).
第三步：化合物83与化合物84的制备Step 3: Preparation of Compound 83 and Compound 84
在氮气氛围下，向反应瓶中分别加入上述粗品83b-1与83b-2的混合物(0.50g)、上述粗品中间体1(0.60g)、PdCl2(PPh3)2(83mg,0.12mmol)、CuI(45mg,0.24mmol)和DIPEA(0.46g,3.56mmol)，加入10mL DMF，60℃反应5h。将反应体系冷却至室温，加入到40mL水中，过滤，将滤饼过SFC(仪器及制备柱：采用SFC Prep 150AP制备液相，制备柱型号是Torus DEA，内径×长度＝19mm×250mm)。制备方法：粗品的DMF溶液用0.45μm滤膜过滤，制备成样品液。流动相体系：二氧化碳/甲醇。洗脱方法：等度洗脱，流动相甲醇含量35％，流量30mL/min。即可得到化合物83(洗脱时间8.12min)(25mg，从化合物83a算两步收率：13％)与化合物84(洗 脱时间9.87min)(60mg，从化合物83a算两步收率：31％)。Under a nitrogen atmosphere, the mixture of the above-mentioned crude products 83b-1 and 83b-2 (0.50g), the above-mentioned crude intermediate 1 (0.60g), and PdCl 2 (PPh 3 ) 2 (83mg, 0.12mmol) were added to the reaction bottle respectively. , CuI (45mg, 0.24mmol) and DIPEA (0.46g, 3.56mmol), add 10mL DMF, and react at 60°C for 5h. Cool the reaction system to room temperature, add it to 40 mL of water, filter, and pass the filter cake through SFC (instrument and preparation column: use SFC Prep 150AP to prepare the liquid phase, the preparation column model is Torus DEA, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the crude DMF solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: carbon dioxide/methanol. Elution method: isocratic elution, mobile phase methanol content 35%, flow rate 30mL/min. Compound 83 (elution time 8.12 min) (25 mg, two-step yield calculated from compound 83a: 13%) and compound 84 (elution time: 13%) can be obtained. Removal time: 9.87 min) (60 mg, two-step yield calculated from compound 83a: 31%).
化合物83的核磁数据：NMR data of compound 83:
1H NMR(400MHz,CDCl3)δ8.32(d,1H),7.96(d,2H),7.71(d,1H),7.59(d,1H),7.36–7.30(m,1H),7.22(dd,1H),6.67(d,1H),6.57(d,1H),6.46(dd,1H),4.96(dd,1H),4.23–4.16(m,2H),3.86–3.77(m,2H),3.73–3.64(m,1H),2.97–2.65(m,3H),2.25–2.15(m,1H),1.97(s,6H),1.36–1.26(m,1H),0.70–0.60(m,2H),0.45–0.34(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.32(d,1H),7.96(d,2H),7.71(d,1H),7.59(d,1H),7.36–7.30(m,1H),7.22( dd,1H),6.67(d,1H),6.57(d,1H),6.46(dd,1H),4.96(dd,1H),4.23–4.16(m,2H),3.86–3.77(m,2H) ,3.73–3.64(m,1H),2.97–2.65(m,3H),2.25–2.15(m,1H),1.97(s,6H),1.36–1.26(m,1H),0.70–0.60(m, 2H),0.45–0.34(m,2H).
LCMS m/z＝630.5[M+1]+ LCMS m/z＝630.5[M+1] +
化合物84的核磁数据：NMR data of compound 84:
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.39(d,1H),7.98(s,1H),7.69(d,1H),7.66(d,1H),7.48(dd,1H),7.38–7.34(m,1H),6.83(d,1H),6.58(dd,1H),6.49(d,1H),4.95(dd,1H),4.43–4.35(m,2H),4.14–4.07(m,2H),3.89–3.78(m,1H),2.98–2.65(m,3H),2.19–2.10(m,1H),1.97(s,6H),1.58–1.46(m,1H),1.08–1.02(m,2H),0.60–0.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.22(s,1H),8.39(d,1H),7.98(s,1H),7.69(d,1H),7.66(d,1H),7.48(dd, 1H),7.38–7.34(m,1H),6.83(d,1H),6.58(dd,1H),6.49(d,1H),4.95(dd,1H),4.43–4.35(m,2H),4.14 –4.07(m,2H),3.89–3.78(m,1H),2.98–2.65(m,3H),2.19–2.10(m,1H),1.97(s,6H),1.58–1.46(m,1H) ,1.08–1.02(m,2H),0.60–0.54(m,2H).
LCMS m/z＝630.5[M+1]+ LCMS m/z＝630.5[M+1] +
实施例85：化合物85的制备
Example 85: Preparation of Compound 85
以化合物85d为原料，参考实施例81得到化合物85(13mg)。Using compound 85d as a raw material, compound 85 (13 mg) was obtained with reference to Example 81.
1H NMR(400MHz,CDCl3)δ8.48(d,1H),7.97(s,1H),7.90(s,1H),7.69(d,1H),7.56–7.28(m,4H),7.15(dd,1H),6.85–6.80(m,1H),6.58(dd,1H),5.00–4.90(m,1H),4.44–4.34(m,2H),4.17–4.05(m,2H),3.92–3.80(m,1H),2.97–2.65(m,3H),2.21–2.07(m,1H),1.69(s,6H),1.34–1.22(m,1H),0.57–0.48(m,2H),0.41–0.33(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.48(d,1H),7.97(s,1H),7.90(s,1H),7.69(d,1H),7.56–7.28(m,4H),7.15( dd,1H),6.85–6.80(m,1H),6.58(dd,1H),5.00–4.90(m,1H),4.44–4.34(m,2H),4.17–4.05(m,2H),3.92– 3.80(m,1H),2.97–2.65(m,3H),2.21–2.07(m,1H),1.69(s,6H),1.34–1.22(m,1H),0.57–0.48(m,2H), 0.41–0.33(m,2H).
实施例86：化合物86的制备
Example 86: Preparation of Compound 86
以化合物88b为原料，参考实施例50得到化合物86(0.07g)。Using compound 88b as a raw material, compound 86 (0.07g) was obtained with reference to Example 50.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.41(d,1H),8.02(s,1H),7.96–7.90(m,2H),7.69(d,1H),7.54–7.42(m,3H),7.39–7.34(m,1H),7.32–7.26(m,2H),7.03–6.96(m,1H),6.73(dd,1H),4.99–4.89(m,1H),3.94–3.82(m,1H),3.74–3.43(m,4H),2.95–2.66(m,3H),2.60–2.44(m,1H),2.31–2.08(m,2H),2.02(s,6H),1.59–1.46(m,1H),1.02–0.90(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.21(s,1H),8.41(d,1H),8.02(s,1H),7.96–7.90(m,2H),7.69(d,1H),7.54– 7.42(m,3H),7.39–7.34(m,1H),7.32–7.26(m,2H),7.03–6.96(m,1H),6.73(dd,1H),4.99–4.89(m,1H), 3.94–3.82(m,1H),3.74–3.43(m,4H),2.95–2.66(m,3H),2.60–2.44(m,1H),2.31–2.08(m,2H),2.02(s,6H ),1.59–1.46(m,1H),1.02–0.90(m,2H),0.60–0.52(m,2H).
实施例87：化合物87的制备
Example 87: Preparation of Compound 87
以化合物90b为原料，参考实施例50得到化合物87(0.06g)。Using compound 90b as a raw material, compound 87 (0.06g) was obtained with reference to Example 50.
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.58(d,1H),8.10–7.96(m,2H),7.81(s,1H),7.71(d,1H),7.60–7.41(m,4H),7.36(s,1H),7.27–7.21(m,2H),7.16(d,1H),5.00–4.91(m,1H),4.18–4.02(m,2H),3.20–3.00(m,4H),2.98–2.65(m,6H),2.35–1.77(m,7H). 1 H NMR (400MHz, CDCl 3 ) δ8.76(s,1H),8.58(d,1H),8.10–7.96(m,2H),7.81(s,1H),7.71(d,1H),7.60– 7.41(m,4H),7.36(s,1H),7.27–7.21(m,2H),7.16(d,1H),5.00–4.91(m,1H),4.18–4.02(m,2H),3.20– 3.00(m,4H),2.98–2.65(m,6H),2.35–1.77(m,7H).
实施例88：化合物88的制备
Example 88: Preparation of Compound 88
以化合物88b为原料，参考实施例50得到化合物88(0.07g)。Using compound 88b as a raw material, compound 88 (0.07g) was obtained with reference to Example 50.
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.58(d,1H),8.01(s,2H),7.83(s,1H),7.69(d,1H),7.62–7.42(m,4H),7.32–7.26(m,2H),7.03–6.95(m,1H),6.73(dd,1H),5.00–4.88(m,1H),3.93–3.80(m,1H),3.73–3.42(m,4H),3.19–3.05(m,2H),2.96–2.64(m,5H),2.58–2.44(m,1H),2.38–2.02(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.77(s,1H),8.58(d,1H),8.01(s,2H),7.83(s,1H),7.69(d,1H),7.62–7.42( m,4H),7.32–7.26(m,2H),7.03–6.95(m,1H),6.73(dd,1H),5.00–4.88(m,1H),3.93–3.80(m,1H),3.73– 3.42(m,4H),3.19–3.05(m,2H),2.96–2.64(m,5H),2.58–2.44(m,1H),2.38–2.02(m,4H).
实施例89：化合物89的制备
Example 89: Preparation of Compound 89
以化合物89c为原料，参考实施例81得到化合物89(75mg)。Using compound 89c as a raw material, compound 89 (75 mg) was obtained with reference to Example 81.
1H NMR(400MHz,CDCl3)δ9.89(s,1H),8.64–8.58(m,1H),8.42(d,1H),7.95(s,1H),7.80–7.63(m,2H),7.52–7.35(m,3H),6.87–6.80(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H),3.94–3.82(m,1H),2.96–2.66(m,3H),2.19–2.08(m,1H),1.77(s,6H),1.73–1.63(m,1H),1.13–1.02(m,2H),0.70–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.89(s,1H),8.64–8.58(m,1H),8.42(d,1H),7.95(s,1H),7.80–7.63(m,2H), 7.52–7.35(m,3H),6.87–6.80(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H ),3.94–3.82(m,1H),2.96–2.66(m,3H),2.19–2.08(m,1H),1.77(s,6H),1.73–1.63(m,1H),1.13–1.02(m ,2H),0.70–0.62(m,2H).
LCMS m/z＝641.2[M+1]+ LCMS m/z＝641.2[M+1] +
实施例90：化合物90的制备
Example 90: Preparation of Compound 90
以化合物90b为原料，参考实施例50得到化合物90(0.085g)。Using compound 90b as a raw material, compound 90 (0.085g) was obtained with reference to Example 50.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.41(d,1H),8.11(s,1H),7.91(d,2H),7.70(d,1H),7.53–7.40(m,3H),7.39–7.30(m,2H),7.27–7.20(m,2H),7.11(dd,1H),5.00–4.90(m,1H),4.18–4.02(m,2H),3.20–3.02(m,2H),2.97–2.65(m,4H),2.20–2.08(m,1H),2.08–1.93(m,8H),1.92–1.75(m,2H),1.57–1.45(m,1H),1.02–0.90(m,2H),0.60–0.51(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.19(s,1H),8.41(d,1H),8.11(s,1H),7.91(d,2H),7.70(d,1H),7.53–7.40( m,3H),7.39–7.30(m,2H),7.27–7.20(m,2H),7.11(dd,1H),5.00–4.90(m,1H),4.18–4.02(m,2H),3.20– 3.02(m,2H),2.97–2.65(m,4H),2.20–2.08(m,1H),2.08–1.93(m,8H),1.92–1.75(m,2H),1.57–1.45(m,1H ),1.02–0.90(m,2H),0.60–0.51(m,2H).
实施例91：化合物91的制备
Example 91: Preparation of Compound 91
第一步：91b的制备Step One: Preparation of 91b
向反应瓶中依次加入91a(0.20g，1.14mmol)、91A的盐酸盐(0.16g)、碳酸铯(1.08g，3.31mmol)和DMF(5mL)，室温反应15h。向反应液中加入30mL乙酸乙酯和20mL水，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:10)，得到91b(0.22g，产率：84％)。Add 91a (0.20g, 1.14mmol), 91A hydrochloride (0.16g), cesium carbonate (1.08g, 3.31mmol) and DMF (5mL) in sequence to the reaction bottle, and react at room temperature for 15h. Add 30 mL of ethyl acetate and 20 mL of water to the reaction solution, wash the organic phase with saturated sodium chloride aqueous solution (10 mL Petroleum ether (v/v) = 1:20-1:10) to obtain 91b (0.22g, yield: 84%).
第二步：91c的制备Step 2: Preparation of 91c
向反应瓶中加入91b(0.22g，0.95mmol)、锌粉(0.62g，9.54mmol)、氯化铵(0.51g，9.53mmol)、四氢呋喃(9mL)和水(3mL)，室温反应1h。将反应体系垫硅藻土过滤，将滤饼用50mL乙酸乙酯洗涤，向滤液中加入50mL水和50mL乙酸乙酯，有机相用无水硫酸钠干燥，减压浓缩，得粗品91c(0.19g)。Add 91b (0.22g, 0.95mmol), zinc powder (0.62g, 9.54mmol), ammonium chloride (0.51g, 9.53mmol), tetrahydrofuran (9mL) and water (3mL) to the reaction bottle, and react at room temperature for 1h. The reaction system was filtered through diatomaceous earth, and the filter cake was washed with 50 mL of ethyl acetate. 50 mL of water and 50 mL of ethyl acetate were added to the filtrate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 91c (0.19 g). ).
以化合物91c为原料，参考实施例19得到化合物91(0.12g)。Using compound 91c as a raw material, compound 91 (0.12g) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.15(s,1H),8.00(d,1H),7.82–7.74(m,2H),7.67(d,1H),6.83–6.78(m,1H),6.55(dd,1H),6.44–6.38(m,1H),6.33(dd,1H),5.52–5.25(m,1H),4.98–4.87(m,1H),4.42–4.30(m,2H),4.22–4.02(m,4H),3.98–3.73(m,3H),2.95–2.66(m,3H),2.18–2.07(m,1H),1.93(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.40(s,1H),8.15(s,1H),8.00(d,1H),7.82–7.74(m,2H),7.67(d,1H),6.83– 6.78(m,1H),6.55(dd,1H),6.44–6.38(m,1H),6.33(dd,1H),5.52–5.25(m,1H),4.98–4.87(m,1H),4.42– 4.30(m,2H),4.22–4.02(m,4H),3.98–3.73(m,3H),2.95–2.66(m,3H),2.18–2.07(m,1H),1.93(s,6H).
实施例92：化合物92三氟乙酸盐的制备
Example 92: Preparation of compound 92 trifluoroacetate salt
以化合物92b为原料，参考实施例19制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物92的三氟乙酸盐(255mg)。Using compound 92b as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 92 (255 mg).
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.16(d,1H),7.98(s,1H),7.83–7.74(m,2H),7.67(d,1H),7.20–7.14(m,1H),7.13–7.05(m,1H),6.84–6.76(m,1H),6.60–6.50(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.00(m,2H),3.88–3.75(m,1H),2.97–2.65(m,4H),2.20–2.07(m,1H),1.94(s,6H),1.19(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.63(s,1H),8.16(d,1H),7.98(s,1H),7.83–7.74(m,2H),7.67(d,1H),7.20– 7.14(m,1H),7.13–7.05(m,1H),6.84–6.76(m,1H),6.60–6.50(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H ),4.14–4.00(m,2H),3.88–3.75(m,1H),2.97–2.65(m,4H),2.20–2.07(m,1H),1.94(s,6H),1.19(d,6H ).
LCMS m/z＝641.1[M+1]+ LCMS m/z＝641.1[M+1] +
实施例93：化合物93三氟乙酸盐的制备
Example 93: Preparation of compound 93 trifluoroacetate salt
以化合物93a为原料，参考实施例19制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物93的三氟乙酸盐(220mg)。Using compound 93a as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 93 (220 mg).
1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.16(d,1H),8.05–7.95(m,1H),7.83–7.75(m,2H),7.67(d,1H),7.13–7.07(m,1H),7.01(dd,1H),6.83–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.66(m,3H),2.39(d,2H),2.18–2.07(m,1H),1.94(s,6H),1.87–1.73(m,1H),0.86(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.65(s,1H),8.16(d,1H),8.05–7.95(m,1H),7.83–7.75(m,2H),7.67(d,1H), 7.13–7.07(m,1H),7.01(dd,1H),6.83–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H), 4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.66(m,3H),2.39(d,2H),2.18–2.07(m,1H),1.94(s,6H), 1.87–1.73(m,1H),0.86(d,6H).
LCMS m/z＝655.1[M+1]+ LCMS m/z＝655.1[M+1] +
实施例94：化合物94的制备
Example 94: Preparation of Compound 94
第一步：94b的制备Step 1: Preparation of 94b
将94a(0.2g，0.9mmol)溶于5mL甲苯中，加入94A(0.2g，0.91mmol)和TEA(0.14g，1.38mmol)，55℃反应2h。将反应体系冷却至室温，抽滤，收集滤饼，得粗品94b(0.21g)。Dissolve 94a (0.2g, 0.9mmol) in 5 mL of toluene, add 94A (0.2g, 0.91mmol) and TEA (0.14g, 1.38mmol), and react at 55°C for 2 hours. The reaction system was cooled to room temperature, filtered with suction, and the filter cake was collected to obtain crude product 94b (0.21g).
LCMS m/z＝441.2[M+1]+ LCMS m/z＝441.2[M+1] +
第二步：化合物94的制备Step 2: Preparation of Compound 94
将上述粗品94b(0.289g)、上述粗品中间体1(0.33g)、TEA(0.20g，1.98mmol)、CuI(25mg，0.13mmol)和PdCl2(PPh3)2(93mg，0.13mmol)加入到反应瓶中，加入8mL DMF，氮气氛围下55℃反应3h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100 mL DCM/MeOH(v/v)＝5:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1-1:1)，得化合物94(120mg，从化合物94a算两步收率：15％)。The above crude product 94b (0.289g), the above crude intermediate 1 (0.33g), TEA (0.20g, 1.98mmol), CuI (25mg, 0.13mmol) and PdCl 2 (PPh 3 ) 2 (93mg, 0.13mmol) were added To the reaction bottle, add 8 mL DMF and react at 55°C for 3 hours under nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, and wash the filter cake with 100 Dissolve in mL DCM/MeOH (v/v)=5:1 mixed solvent, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v)=5: 1-1:1), compound 94 (120 mg, two-step yield calculated from compound 94a: 15%) was obtained.
1H NMR(400MHz,CDCl3)δ8.47–8.40(m,1H),8.15(s,1H),7.68–7.57(m,2H),7.54–7.47(m,1H),7.44–7.27(m,6H),6.68–6.64(m,1H),6.51(dd,1H),5.01–4.92(m,1H),4.38–4.27(m,2H),4.14–4.01(m,2H),3.91–3.77(m,1H),2.99–2.67(m,3H),2.19–2.10(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.47–8.40(m,1H),8.15(s,1H),7.68–7.57(m,2H),7.54–7.47(m,1H),7.44–7.27(m ,6H),6.68–6.64(m,1H),6.51(dd,1H),5.01–4.92(m,1H),4.38–4.27(m,2H),4.14–4.01(m,2H),3.91–3.77 (m,1H),2.99–2.67(m,3H),2.19–2.10(m,1H).
LCMS m/z＝650.2[M+1]+ LCMS m/z＝650.2[M+1] +
实施例95：化合物95三氟乙酸盐的制备
Example 95: Preparation of compound 95 trifluoroacetate salt
以95b为原料，参考实施例19制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物95的三氟乙酸盐(215mg)。Use 95b as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 95 (215 mg).
1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.37(d,1H),7.98(s,1H),7.85–7.77(m,2H),7.67(d,1H),7.60–7.30(m,7H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.97–2.63(m,3H),2.18–2.08(m,1H),1.97(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.84(s,1H),8.37(d,1H),7.98(s,1H),7.85–7.77(m,2H),7.67(d,1H),7.60– 7.30(m,7H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.02(m,2H), 3.88–3.75(m,1H),2.97–2.63(m,3H),2.18–2.08(m,1H),1.97(s,6H).
LCMS m/z＝675.3[M+1]+ LCMS m/z＝675.3[M+1] +
实施例96：化合物96的制备
Example 96: Preparation of Compound 96
以96a为原料，参考实施例19得到化合物96(0.20g)。Using 96a as a raw material, compound 96 (0.20 g) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.43(d,1H),8.13(d,1H),7.95(s,1H),7.84(s,2H),7.80(d,1H),7.75(d,1H),7.67(d,1H),7.59–7.53(m,1H),7.49–7.43(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.97–4.89(m,1H),4.40–4.32(m,2H),4.12–4.04(m,2H),3.88–3.77(m,1H),2.95–2.62(m,3H),2.18–2.08(m,1H),1.99(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.00(s,1H),8.43(d,1H),8.13(d,1H),7.95(s,1H),7.84(s,2H),7.80(d, 1H),7.75(d,1H),7.67(d,1H),7.59–7.53(m,1H),7.49–7.43(m,1H),6.84–6.78(m,1H),6.55(dd,1H) ,4.97–4.89(m,1H),4.40–4.32(m,2H),4.12–4.04(m,2H),3.88–3.77(m,1H),2.95–2.62(m,3H),2.18–2.08( m,1H),1.99(s,6H).
实施例97：化合物97的制备
Example 97: Preparation of Compound 97
以化合物97b为原料，参考实施例19得到化合物97(220mg)。 Using compound 97b as a raw material, compound 97 (220 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.42(d,1H),7.94(s,1H),7.86(d,1H),7.83–7.74(m,3H),7.73–7.62(m,2H),7.52(dd,1H),6.84–6.77(m,1H),6.55(dd,1H),6.50–6.43(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.87–3.76(m,1H),2.96–2.62(m,3H),2.18–2.08(m,1H),1.96(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.91(s,1H),8.42(d,1H),7.94(s,1H),7.86(d,1H),7.83–7.74(m,3H),7.73– 7.62(m,2H),7.52(dd,1H),6.84–6.77(m,1H),6.55(dd,1H),6.50–6.43(m,1H),4.98–4.89(m,1H),4.42– 4.30(m,2H),4.13–4.02(m,2H),3.87–3.76(m,1H),2.96–2.62(m,3H),2.18–2.08(m,1H),1.96(s,6H).
实施例98：化合物98三氟乙酸盐的制备
Example 98: Preparation of compound 98 trifluoroacetate salt
第一步：98b的制备Step 1: Preparation of 98b
将98a(1.1g，5mmol)加入到20mL DMF中，加入28B(2.2g，6.17mmol)和碳酸铯(3.3g，10.1mmol)，85℃反应3h。将反应液冷却至室温，加入100mL乙酸乙酯和200mL纯化水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝3:1)，得98b(0.6g，收率：24％)。Add 98a (1.1g, 5mmol) to 20mL DMF, add 28B (2.2g, 6.17mmol) and cesium carbonate (3.3g, 10.1mmol), and react at 85°C for 3 hours. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 200 mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 3:1), 98b (0.6g, yield: 24%) was obtained.
第二步：化合物98三氟乙酸盐的制备Step 2: Preparation of compound 98 trifluoroacetate salt
将98b(0.2g，0.4mmol)溶于5mL DMF中，依次加入上述粗品中间体1(0.17g)、TEA(0.1g，0.99mmol)、CuI(0.019g，0.1mmol)和PdCl2(PPh3)2(0.07g，0.1mmol)，氮气氛围下95℃反应1h。将反应液冷却至室温，加入20mL水，过滤，将滤饼用10mL水洗涤，将滤饼用30mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:3)，所得粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得化合物98的三氟乙酸盐(0.02g)。Dissolve 98b (0.2g, 0.4mmol) in 5mL DMF, and add the above crude intermediate 1 (0.17g), TEA (0.1g, 0.99mmol), CuI (0.019g, 0.1mmol) and PdCl 2 (PPh 3 ) 2 (0.07g, 0.1mmol), react at 95°C for 1 hour under nitrogen atmosphere. Cool the reaction solution to room temperature, add 20 mL of water, filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 30 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ Ethyl acetate (v/v) = 1:3), and the crude product obtained was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 98 (0.02g).
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.51(d,1H),8.09(s,1H),7.98(s,1H),7.70(d,1H),7.65–7.58(m,1H),7.57–7.49(m,1H),6.88–6.80(m,1H),6.59(dd,1H),4.99–4.89(m,1H),4.48–4.37(m,2H),4.23–4.11(m,2H),3.98–3.87(m,1H),3.20–2.66(m,7H),2.33–2.04(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.74(s,1H),8.51(d,1H),8.09(s,1H),7.98(s,1H),7.70(d,1H),7.65–7.58( m,1H),7.57–7.49(m,1H),6.88–6.80(m,1H),6.59(dd,1H),4.99–4.89(m,1H),4.48–4.37(m,2H),4.23– 4.11(m,2H),3.98–3.87(m,1H),3.20–2.66(m,7H),2.33–2.04(m,3H).
实施例99：化合物99三氟乙酸盐的制备
Example 99: Preparation of compound 99 trifluoroacetate salt
以99b为原料，参考实施例92制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物99的三氟乙酸盐(185mg)。Use 99b as raw material, refer to the preparation method of Example 92, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 99 (185 mg).
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.19–8.08(m,2H),7.84–7.75(m,2H),7.67(d,1H),7.17–7.12(m,1H),7.09–7.03(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.87–3.75(m,1H),2.95–2.65(m,3H),2.57(q,2H),2.20–2.05 (m,1H),1.94(s,6H),1.18(t,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.63(s,1H),8.19–8.08(m,2H),7.84–7.75(m,2H),7.67(d,1H),7.17–7.12(m,1H ),7.09–7.03(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.40–4.30(m,2H),4.13–4.02(m ,2H),3.87–3.75(m,1H),2.95–2.65(m,3H),2.57(q,2H),2.20–2.05 (m,1H),1.94(s,6H),1.18(t,3H).
LCMS m/z＝627.0[M+1]+ LCMS m/z＝627.0[M+1] +
实施例100与101：化合物100与101的制备
Examples 100 and 101: Preparation of Compounds 100 and 101
以化合物100a为原料，参考实施例83与84得到化合物100与化合物101Using compound 100a as raw material, compound 100 and compound 101 were obtained with reference to Examples 83 and 84.
终产物提纯方法：SFC(仪器及制备柱：采用SFC Prep 150 AP制备液相，制备柱型号是大赛璐Torus 2-pic，内径×长度＝19mm×250mm)。制备方法：粗品的甲醇溶液用0.45μm滤膜过滤，制备成样品液。流动相体系：二氧化碳/甲醇。洗脱方法：等度洗脱，流动相甲醇含量20％，流量40mL/min，分别得到化合物100(洗脱时间7.57min)(50mg)与化合物101(洗脱时间11.53min)(190mg)。Final product purification method: SFC (instrument and preparation column: SFC Prep 150 AP is used to prepare the liquid phase. The preparation column model is Daicel Torus 2-pic, inner diameter × length = 19mm × 250mm). Preparation method: The methanol solution of the crude product is filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: carbon dioxide/methanol. Elution method: isocratic elution, mobile phase methanol content 20%, flow rate 40mL/min, compound 100 (elution time 7.57min) (50mg) and compound 101 (elution time 11.53min) (190mg) were obtained respectively.
化合物100的核磁氢谱：Proton NMR spectrum of compound 100:
1H NMR(400MHz,CDCl3)δ8.34(d,1H),8.05–7.95(m,2H),7.71(d,1H),7.47–7.41(m,1H),7.35–7.30(m,1H),7.22(dd,1H),6.71–6.65(m,1H),6.47(dd,1H),5.00–4.91(m,1H),4.26–4.18(m,2H),3.85–3.67(m,3H),2.96–2.66(m,3H),2.25–2.14(m,1H),2.10(s,3H),1.94(s,6H),1.36–1.23(m,1H),0.69–0.61(m,2H),0.44–0.35(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.34(d,1H),8.05–7.95(m,2H),7.71(d,1H),7.47–7.41(m,1H),7.35–7.30(m,1H ),7.22(dd,1H),6.71–6.65(m,1H),6.47(dd,1H),5.00–4.91(m,1H),4.26–4.18(m,2H),3.85–3.67(m,3H ),2.96–2.66(m,3H),2.25–2.14(m,1H),2.10(s,3H),1.94(s,6H),1.36–1.23(m,1H),0.69–0.61(m,2H ),0.44–0.35(m,2H).
LCMS m/z＝644.1[M+1]+ LCMS m/z＝644.1[M+1] +
化合物101的核磁氢谱：Proton NMR spectrum of compound 101:
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.39(d,1H),7.96(s,1H),7.70(d,1H),7.54–7.43(m,2H),7.38–7.33(m,1H),6.86–6.81(m,1H),6.58(dd,1H),5.00–4.90(m,1H),4.47–4.36(m,2H),4.17–4.05(m,2H),3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.07(m,4H),1.94(s,6H),1.59–1.46(m,1H),1.10–0.99(m,2H),0.62–0.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.24(s,1H),8.39(d,1H),7.96(s,1H),7.70(d,1H),7.54–7.43(m,2H),7.38– 7.33(m,1H),6.86–6.81(m,1H),6.58(dd,1H),5.00–4.90(m,1H),4.47–4.36(m,2H),4.17–4.05(m,2H), 3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.07(m,4H),1.94(s,6H),1.59–1.46(m,1H),1.10–0.99(m,2H ),0.62–0.54(m,2H).
LCMS m/z＝644.0[M+1]+ LCMS m/z＝644.0[M+1] +
实施例102：化合物102的制备
Example 102: Preparation of Compound 102
第一步：102b的制备Step One: Preparation of 102b
将102a(4.7g，22.6mmol)溶解于80mL DCM中，加入TEA(4.58g，45.26mmol)与DMAP(0.28g，2.29mmol)，0℃缓慢滴加三氟乙酸酐(5.70g，27.14mmol)，室温反应3h。向反应体系中加入100mL饱和碳酸氢钠水溶液，用200mL DCM萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到102b(6.5g，收率：95％)。Dissolve 102a (4.7g, 22.6mmol) in 80mL DCM, add TEA (4.58g, 45.26mmol) and DMAP (0.28g, 2.29mmol), and slowly add trifluoroacetic anhydride (5.70g, 27.14mmol) at 0°C. , react at room temperature for 3h. Add 100 mL saturated sodium bicarbonate aqueous solution to the reaction system, extract with 200 mL DCM, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v /v)=3:1), 102b (6.5g, yield: 95%) was obtained.
第二步：102c的制备Step 2: Preparation of 102c
将102b(6.08g，20.00mmol)与3-碘氮杂环丁-1-甲酸叔丁酯(6.79g，23.98mmol)溶解于80mL DMA中，加入锌粉(7.85g，120.8mmol)，氮气氛围下加入2-脒基吡啶盐酸盐(CAS:51285-26-8)(0.63g，4.0mmol)与氯化镍乙二醇二甲醚络合物(CAS:29046-78-4)(0.88g，4.00mmol)，氮气氛围下100℃反应16h。将反应体系冷却至室温，加入200mL水和100mL乙酸乙酯，过滤，将滤液分液，水相用200mL乙酸乙酯萃取，有机相用100mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到102c(4.3g，收率：57％)。Dissolve 102b (6.08g, 20.00mmol) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (6.79g, 23.98mmol) in 80mL DMA, add zinc powder (7.85g, 120.8mmol), and create a nitrogen atmosphere Add 2-amidinopyridine hydrochloride (CAS: 51285-26-8) (0.63g, 4.0mmol) and nickel chloride glycol dimethyl ether complex (CAS: 29046-78-4) (0.88 g, 4.00mmol), reacted at 100°C for 16h under nitrogen atmosphere. Cool the reaction system to room temperature, add 200 mL water and 100 mL ethyl acetate, filter, separate the filtrate, extract the aqueous phase with 200 mL ethyl acetate, wash the organic phase with 100 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product. Separate and purify by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 102c (4.3 g, yield: 57%).
第三步：102d的制备Step 3: Preparation of 102d
将102c(4.3g，11.31mmol)溶解于80mL甲醇中，加入碳酸钾(9.38g，67.87mmol)与碳酸铯(7.37g，22.62mmol)，60℃反应16h。将反应体系冷却至室温，加入150mL DCM，过滤，将滤液减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到102d(2.4g，收率：75％)。Dissolve 102c (4.3g, 11.31mmol) in 80mL methanol, add potassium carbonate (9.38g, 67.87mmol) and cesium carbonate (7.37g, 22.62mmol), and react at 60°C for 16h. The reaction system was cooled to room temperature, 150 mL DCM was added, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2:1) to obtain 102d (2.4g, Yield: 75%).
第四步：102e的制备Step 4: Preparation of 102e
将102d(1.8g，6.33mmol)溶解于60mL乙腈中，加入KI(1.58g，9.52mmol)与CuI(1.81g，9.50mmol)和I2(2.41g，9.50mmol)，氮气氛围下0℃缓慢滴加亚硝酸异戊酯(1.11g，9.48mmol)，室温反应16h。向反应体系中加入100mL饱和硫代硫酸钠水溶液，过滤，将滤液用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到102e(1.2g，收率：48％)。Dissolve 102d (1.8g, 6.33mmol) in 60mL acetonitrile, add KI (1.58g, 9.52mmol), CuI (1.81g, 9.50mmol) and I 2 (2.41g, 9.50mmol) slowly at 0°C under nitrogen atmosphere Isoamyl nitrite (1.11g, 9.48mmol) was added dropwise, and the reaction was carried out at room temperature for 16 hours. Add 100 mL of saturated sodium thiosulfate aqueous solution to the reaction system, filter, extract the filtrate with 100 mL of ethyl acetate, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum) Ether/ethyl acetate (v/v)=3:1), 102e (1.2g, yield: 48%) was obtained.
第五步：102f的制备Step 5: Preparation of 102f
将102e(1.2g，3.04mmol)、4-吡唑硼酸频哪醇酯(CAS:269410-08-4)(0.88g，4.54mmol)、碳酸钾(0.84g，6.08mmol)，氮气氛围下加入[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(250mg，0.31mmol)，氮气氛围下100℃反应4h。将反应液冷却至室温，加入80mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到102f(520mg，收率：51％)。102e (1.2g, 3.04mmol), 4-pyrazole boric acid pinacol ester (CAS: 269410-08-4) (0.88g, 4.54mmol), and potassium carbonate (0.84g, 6.08mmol) were added under nitrogen atmosphere. [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (250 mg, 0.31 mmol), react at 100°C for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 80 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate ( v/v)=3:1), 102f (520 mg, yield: 51%) was obtained.
LCMS m/z＝336.1[M+1]+ LCMS m/z＝336.1[M+1] +
第六步：102g的制备Step 6: Preparation of 102g
将102f(0.072g，0.21mmol)溶解于8mL乙腈中，加入碳酸铯(0.14g，0.43mmol)与53B(0.32g，1.04mmol)，80℃反应8h。将反应体系冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到102g(90mg，收率：76％)。Dissolve 102f (0.072g, 0.21mmol) in 8 mL acetonitrile, add cesium carbonate (0.14g, 0.43mmol) and 53B (0.32g, 1.04mmol), and react at 80°C for 8 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 102g (90 mg, yield: 76%). ).
LCMS m/z＝562.2[M+1]+ LCMS m/z＝562.2[M+1] +
以化合物102g为原料，参考实施例23得到化合物102(40mg)。 Using compound 102g as a raw material, compound 102 (40 mg) was obtained with reference to Example 23.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.40(d,1H),8.09–8.05(m,1H),8.00(s,1H),7.92(s,1H),7.70(d,1H),7.49(dd,1H),7.40–7.32(m,1H),7.27–7.14(m,2H),6.90–6.84(m,1H),6.62(dd,1H),5.00–4.86(m,1H),4.56–4.44(m,2H),4.33–4.20(m,1H),4.16–4.05(m,2H),2.96–2.65(m,3H),2.20–2.08(m,1H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.91(m,2H),0.62–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.19(s,1H),8.40(d,1H),8.09–8.05(m,1H),8.00(s,1H),7.92(s,1H),7.70( d,1H),7.49(dd,1H),7.40–7.32(m,1H),7.27–7.14(m,2H),6.90–6.84(m,1H),6.62(dd,1H),5.00–4.86( m,1H),4.56–4.44(m,2H),4.33–4.20(m,1H),4.16–4.05(m,2H),2.96–2.65(m,3H),2.20–2.08(m,1H), 2.03(s,6H),1.58–1.46(m,1H),1.00–0.91(m,2H),0.62–0.52(m,2H).
实施例103：化合物103的制备
Example 103: Preparation of Compound 103
第一步：103b的制备Step One: Preparation of 103b
将103a(450mg,2.0mmol)溶解于10mL二氯甲烷中，加入103A(0.53g，2.42mmol)和TCFH(0.85g,3.03mmol)，加入NMI(0.66g,8.04mmol)，室温反应16h。向反应体系中加入50mL饱和碳酸氢钠水溶液，用100mL二氯甲烷萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝5:1)，得到103b(800mg，收率：94％)。Dissolve 103a (450mg, 2.0mmol) in 10mL dichloromethane, add 103A (0.53g, 2.42mmol) and TCFH (0.85g, 3.03mmol), add NMI (0.66g, 8.04mmol), and react at room temperature for 16h. Add 50 mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract with 100 mL of methylene chloride, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/v)=5:1), 103b (800 mg, yield: 94%) was obtained.
LCMS m/z＝426.1[M+1]+ LCMS m/z＝426.1[M+1] +
第二步：化合物103的制备Step 2: Preparation of Compound 103
将103b(0.21g，0.49mmol)、上述粗品中间体1(0.25g)、TEA(0.15g，1.48mmol)、CuI(10mg，0.053mmol)和PdCl2(PPh3)2(35mg，0.05mmol)加入到反应瓶中，加入4mL DMF，氮气氛围下50℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，将滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:2)，得到化合物103(0.21g，收率：68％)。103b (0.21g, 0.49mmol), the above crude intermediate 1 (0.25g), TEA (0.15g, 1.48mmol), CuI (10mg, 0.053mmol) and PdCl 2 (PPh 3 ) 2 (35mg, 0.05mmol) Add it to the reaction bottle, add 4 mL DMF, and react at 50°C for 2 hours under nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether). /ethyl acetate (v/v)=1:2) to obtain compound 103 (0.21g, yield: 68%).
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.94(s,1H),7.88–7.78(m,2H),7.72(s,1H),7.70–7.60(m,2H),7.58–7.50(m,1H),7.37–7.29(m,1H),7.27–7.21(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.43–4.32(m,2H),4.17–4.06(m,2H),3.93–3.78(m,1H),2.95–2.64(m,3H),2.19–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.05(s,1H),7.94(s,1H),7.88–7.78(m,2H),7.72(s,1H),7.70–7.60(m,2H), 7.58–7.50(m,1H),7.37–7.29(m,1H),7.27–7.21(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H ),4.43–4.32(m,2H),4.17–4.06(m,2H),3.93–3.78(m,1H),2.95–2.64(m,3H),2.19–2.07(m,1H).
实施例104：化合物104的制备
Example 104: Preparation of Compound 104
第一步：104b的制备Step One: Preparation of 104b
将104a(1.00g，7.57mmol)溶于15mL二氯甲烷中，氮气氛围下-15℃缓慢滴加溴素(1.21g，7.57mmol)的5mL二氯甲烷溶液，-15℃反应0.5h。-15℃向反应液加入30mL饱和碳酸氢钠水溶液，水相用二氯甲烷萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝5:1)，得104b(1.30g，收率：81％)。Dissolve 104a (1.00g, 7.57mmol) in 15mL dichloromethane, slowly drop bromine (1.21g, 7.57mmol) in 5mL dichloromethane at -15°C under a nitrogen atmosphere, and react at -15°C for 0.5h. Add 30 mL saturated sodium bicarbonate aqueous solution to the reaction solution at -15°C, extract the aqueous phase with dichloromethane (10 mL : Ethyl acetate (v/v)=5:1) to obtain 104b (1.30g, yield: 81%).
LCMS m/z＝211.1[M+1]+ LCMS m/z＝211.1[M+1] +
第二步：参考由16A制备16B的制备方法，以104a为起始原料得到104c(0.74g)Step 2: Refer to the preparation method of preparing 16B from 16A, and use 104a as the starting material to obtain 104c (0.74g)
LCMS m/z＝173.2[M+1]+ LCMS m/z＝173.2[M+1] +
以化合物104c为原料，参考实施例19得到化合物104(0.11g)。Using compound 104c as a raw material, compound 104 (0.11g) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.97(s,1H),7.84(s,1H),7.75(s,1H),7.68(d,1H),7.37–7.30(m,1H),7.18–7.10(m,1H),6.85–6.77(m,1H),6.56(dd,1H),4.99–4.87(m,1H),4.42–4.32(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.07(m,4H),1.97(s,6H),1.70–1.58(m,1H),0.92–0.80(m,2H),0.57–0.47(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.19(s,1H),7.97(s,1H),7.84(s,1H),7.75(s,1H),7.68(d,1H),7.37–7.30( m,1H),7.18–7.10(m,1H),6.85–6.77(m,1H),6.56(dd,1H),4.99–4.87(m,1H),4.42–4.32(m,2H),4.12– 4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.07(m,4H),1.97(s,6H),1.70–1.58(m,1H), 0.92–0.80(m,2H),0.57–0.47(m,2H).
LCMS m/z＝644.3[M+1]+ LCMS m/z＝644.3[M+1] +
实施例105：化合物105的制备
Example 105: Preparation of Compound 105
以化合物105a为原料，参考实施例104得到化合物105(0.24g)。Using compound 105a as a raw material, compound 105 (0.24g) was obtained with reference to Example 104.
1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.44(dd,1H),7.97(s,1H),7.81(s,1H),7.73(s,1H),7.67(d,1H),7.37–7.25(m,2H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.74(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.95(s,6H),1.68–1.55(m,1H),1.18–1.08(m,2H),0.74–0.65(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.90(s,1H),8.44(dd,1H),7.97(s,1H),7.81(s,1H),7.73(s,1H),7.67(d, 1H),7.37–7.25(m,2H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.00( m,2H),3.88–3.74(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.95(s,6H),1.68–1.55(m,1H),1.18– 1.08(m,2H),0.74–0.65(m,2H).
LCMS m/z＝630.2[M+1]+ LCMS m/z＝630.2[M+1] +
实施例106：化合物106的制备
Example 106: Preparation of Compound 106
以化合物106b为原料，参考实施例104得到化合物106(150mg)。Using compound 106b as a raw material, compound 106 (150 mg) was obtained with reference to Example 104.
1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.56–8.50(m,1H),8.24(s,1H),7.82(s,1H),7.72(s,1H),7.67(d,1H),7.38–7.24(m,1H),7.18–7.10(m,1H),6.85–6.75(m,1H),6.55(dd,1H),4.99–4.90(m,1H),4.43–4.30(m,2H),4.12–4.00(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.96(s,6H),1.61–1.49(m,1H),1.04–0.94(m,2H),0.64–0.56(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.96(s,1H),8.56–8.50(m,1H),8.24(s,1H),7.82(s,1H),7.72(s,1H),7.67( d,1H),7.38–7.24(m,1H),7.18–7.10(m,1H),6.85–6.75(m,1H),6.55(dd,1H),4.99–4.90(m,1H),4.43– 4.30(m,2H),4.12–4.00(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.96(s,6H), 1.61–1.49(m,1H),1.04–0.94(m,2H),0.64–0.56(m,2H).
实施例107：化合物107的制备
Example 107: Preparation of Compound 107
以化合物107a为原料，参考实施例104得到化合物107(20mg)。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.06(s,1H),8.35(s,1H),7.94–7.86(m,1H),7.84(s,1H),7.79–7.71(m,1H),7.68(d,1H),6.90–6.83(m,1H),6.72(dd,1H),5.12–5.02(m,1H),4.47–4.32(m,2H),4.07–3.96(m,2H),3.96–3.82(m,1H),2.97–2.80(m,1H),2.67–2.51(m,2H),2.10–1.96(m,1H),1.86(s,6H),1.56–1.44(m,1H),0.98–0.85(m,2H),0.56–0.45(m,2H).Using compound 107a as a raw material, compound 107 (20 mg) was obtained with reference to Example 104. 1 H NMR (400MHz, DMSO-d 6 ) δ11.07(s,1H),9.06(s,1H),8.35(s,1H),7.94–7.86(m,1H),7.84(s,1H), 7.79–7.71(m,1H),7.68(d,1H),6.90–6.83(m,1H),6.72(dd,1H),5.12–5.02(m,1H),4.47–4.32(m,2H), 4.07–3.96(m,2H),3.96–3.82(m,1H),2.97–2.80(m,1H),2.67–2.51(m,2H),2.10–1.96(m,1H),1.86(s,6H ),1.56–1.44(m,1H),0.98–0.85(m,2H),0.56–0.45(m,2H).
LCMS m/z＝646.5[M-1]- LCMS m/z＝646.5[M-1] -
实施例108：化合物108的制备
Example 108: Preparation of Compound 108
以化合物108a为原料，参考实施例104得到化合物108(300mg)。Using compound 108a as a raw material, compound 108 (300 mg) was obtained with reference to Example 104.
1H NMR(400MHz,CDCl3)δ8.50–8.30(m,2H),7.84(s,1H),7.76(s,1H),7.67(d,1H),7.23(dd,1H),7.09(s,1H),6.85–6.75(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.43–4.30(m,2H),4.14–4.00(m,2H),3.88–3.75(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.96(s,6H),1.77–1.64(m,1H),1.02–0.91(m,2H),0.65–0.55(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.50–8.30(m,2H),7.84(s,1H),7.76(s,1H),7.67(d,1H),7.23(dd,1H),7.09( s,1H),6.85–6.75(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.43–4.30(m,2H),4.14–4.00(m,2H),3.88– 3.75(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.96(s,6H),1.77–1.64(m,1H),1.02–0.91(m,2H), 0.65–0.55(m,2H).
实施例109：化合物109的制备
Example 109: Preparation of Compound 109
以化合物109d为原料，参考实施例59得到化合物109(0.15g)。Using compound 109d as a raw material, compound 109 (0.15g) was obtained with reference to Example 59.
1H NMR(400MHz,CDCl3)δ9.94(s,1H),8.28(d,1H),7.95(s,1H),7.74–7.65(m,3H),7.62(d,1H),7.59(s,1H),7.03(dd,1H),6.99–6.95(m,1H),6.85–6.80(m,1H),6.57(dd,1H),6.14(t,1H), 4.99–4.87(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H),3.92–3.78(m,1H),2.98–2.66(m,3H),2.19–2.08(m,1H),1.95–1.79(m,7H),1.02–0.92(m,2H),0.71–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.94(s,1H),8.28(d,1H),7.95(s,1H),7.74–7.65(m,3H),7.62(d,1H),7.59( s,1H),7.03(dd,1H),6.99–6.95(m,1H),6.85–6.80(m,1H),6.57(dd,1H),6.14(t,1H), 4.99–4.87(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H),3.92–3.78(m,1H),2.98–2.66(m,3H),2.19–2.08(m ,1H),1.95–1.79(m,7H),1.02–0.92(m,2H),0.71–0.62(m,2H).
实施例110：化合物110的制备
Example 110: Preparation of Compound 110
以化合物110a为原料，参考实施例102得到化合物110(50mg)。Using compound 110a as a raw material, compound 110 (50 mg) was obtained with reference to Example 102.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.41(d,1H),8.10–7.94(m,3H),7.70(d,1H),7.58–7.46(m,2H),7.39–7.32(m,1H),7.21–7.12(m,2H),6.90–6.84(m,1H),6.62(m,1H),5.00–4.86(m,1H),4.55–4.40(m,2H),4.14–3.95(m,3H),2.96–2.65(m,3H),2.23–2.07(m,1H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.90(m,2H),0.60–0.51(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.18(s,1H),8.41(d,1H),8.10–7.94(m,3H),7.70(d,1H),7.58–7.46(m,2H), 7.39–7.32(m,1H),7.21–7.12(m,2H),6.90–6.84(m,1H),6.62(m,1H),5.00–4.86(m,1H),4.55–4.40(m,2H ),4.14–3.95(m,3H),2.96–2.65(m,3H),2.23–2.07(m,1H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.90(m ,2H),0.60–0.51(m,2H).
实施例111：化合物111的制备
Example 111: Preparation of Compound 111
以化合物111a为原料，参考实施例102得到化合物111(100mg)。Using compound 111a as a raw material, compound 111 (100 mg) was obtained with reference to Example 102.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.41(d,1H),8.03–7.88(m,3H),7.68(d,1H),7.49(dd,1H),7.42–7.28(m,4H),6.90–6.85(m,1H),6.62(dd,1H),4.98–4.87(m,1H),4.55–4.44(m,2H),4.34–4.21(m,1H),4.15–4.05(m,2H),2.95–2.66(m,3H),2.33(s,3H),2.18–2.08(m,1H),2.02(s,6H),1.58–1.45(m,1H),1.00–0.92(m,2H),0.58–0.51(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.21(s,1H),8.41(d,1H),8.03–7.88(m,3H),7.68(d,1H),7.49(dd,1H),7.42– 7.28(m,4H),6.90–6.85(m,1H),6.62(dd,1H),4.98–4.87(m,1H),4.55–4.44(m,2H),4.34–4.21(m,1H), 4.15–4.05(m,2H),2.95–2.66(m,3H),2.33(s,3H),2.18–2.08(m,1H),2.02(s,6H),1.58–1.45(m,1H), 1.00–0.92(m,2H),0.58–0.51(m,2H).
LCMS m/z＝696.2[M+1]+ LCMS m/z＝696.2[M+1] +
实施例112：化合物112三氟乙酸盐的制备
Example 112: Preparation of compound 112 trifluoroacetate salt
以化合物80b为原料，参考实施例22制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物112的三氟乙酸盐(90mg)。Using compound 80b as raw material, refer to the preparation method of Example 22, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 112 (90 mg).
1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.14(d,1H),8.04(s,1H),7.77(s,1H),7.72–7.64(m,2H),7.03–6.98(m,1H),6.94(dd,1H),6.84–6.76(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.86–3.76(m,1H),3.13–2.99(m,2H),2.96–2.65(m,5H),2.31–1.97(m,3H),1.87–1.75(m,1H),0.97–0.90(m,2H),0.68–0.58(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.20(s,1H),8.14(d,1H),8.04(s,1H),7.77(s,1H),7.72–7.64(m,2H),7.03– 6.98(m,1H),6.94(dd,1H),6.84–6.76(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13– 4.02(m,2H),3.86–3.76(m,1H),3.13–2.99(m,2H),2.96–2.65(m,5H),2.31–1.97(m,3H),1.87–1.75(m,1H ),0.97–0.90(m,2H),0.68–0.58(m,2H).
实施例113：化合物113三氟乙酸盐的制备
Example 113: Preparation of compound 113 trifluoroacetate salt
以化合物80c和中间体2为原料，参考实施例19制备方法，经酸性制备[流动相体系：乙腈/水(含0.1％TFA)]，冻干得到化合物113的三氟乙酸盐。Using compound 80c and intermediate 2 as raw materials, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 113.
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.11(d,1H),8.04(s,1H),7.82–7.75(m,2H),7.39(d,1H),7.05–6.99(m,1H),6.94(dd,1H),6.88–6.81(m,1H),4.97–4.87(m,1H),4.55–4.42(m,2H),4.27–4.15(m,2H),3.85–3.74(m,1H),2.97–2.64(m,3H),2.18–2.07(m,1H),1.94(s,6H),1.86–1.76(m,1H),0.98–0.90(m,2H),0.67–0.58(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.61(s,1H),8.11(d,1H),8.04(s,1H),7.82–7.75(m,2H),7.39(d,1H),7.05– 6.99(m,1H),6.94(dd,1H),6.88–6.81(m,1H),4.97–4.87(m,1H),4.55–4.42(m,2H),4.27–4.15(m,2H), 3.85–3.74(m,1H),2.97–2.64(m,3H),2.18–2.07(m,1H),1.94(s,6H),1.86–1.76(m,1H),0.98–0.90(m,2H ),0.67–0.58(m,2H).
实施例114：化合物114的制备
Example 114: Preparation of Compound 114
以化合物28B为原料，参考实施例101得到化合物114(0.17g)。Using compound 28B as a raw material, compound 114 (0.17g) was obtained with reference to Example 101.
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.59–8.52(m,1H),8.01(s,1H),7.69(d,1H),7.60–7.54(m,1H),7.53–7.46(m,1H),7.40–7.34(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.48–4.35(m,2H),4.19–4.08(m,2H),3.98–3.85(m,1H),3.10–2.96(m,2H),2.96–2.65(m,5H),2.31–2.03(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.78(s,1H),8.59–8.52(m,1H),8.01(s,1H),7.69(d,1H),7.60–7.54(m,1H), 7.53–7.46(m,1H),7.40–7.34(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.48–4.35(m,2H ),4.19–4.08(m,2H),3.98–3.85(m,1H),3.10–2.96(m,2H),2.96–2.65(m,5H),2.31–2.03(m,6H).
LCMS m/z＝693.1[M+1]+ LCMS m/z＝693.1[M+1] +
实施例115：化合物115的制备
Example 115: Preparation of Compound 115
第一步：115a的制备Step One: Preparation of 115a
氮气保护下将60％氢化钠(1.06g)加入到20mL DMSO中，缓慢加入85a(2.0g，8.80mmol)和1,3-二溴丙烷(2.66g，13.2mmol)的5mL二氯甲烷溶液，30℃反应19h。向反应体系中加入水(80mL)，用二氯甲烷萃取(80mL×2)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝10:1)，得115a(0.65g，收率：28％)。Add 60% sodium hydride (1.06g) to 20mL DMSO under nitrogen protection, and slowly add 5mL dichloromethane solution of 85a (2.0g, 8.80mmol) and 1,3-dibromopropane (2.66g, 13.2mmol). Reaction at 30°C for 19 hours. Add water (80mL) to the reaction system, extract with dichloromethane (80mL×2), wash the organic phase with saturated aqueous sodium chloride solution (60mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is chromatographed on silica gel. Column separation and purification (petroleum ether:ethyl acetate (v/v)=10:1) gave 115a (0.65g, yield: 28%).
LCMS m/z＝268.4[M+1]+ LCMS m/z＝268.4[M+1] +
第二步：115b的制备Step 2: Preparation of 115b
将115a(0.65g，2.43mmol)溶解于10mL甲醇，加入10％Pd/C(300mg)，置于氢气球氛围下室温反应5h。将反应体系垫硅藻土过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝3:1)，得115b(0.38g，收率：66％)。Dissolve 115a (0.65g, 2.43mmol) in 10mL methanol, add 10% Pd/C (300mg), and react at room temperature for 5 hours under a hydrogen balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=3:1) to obtain 115b (0.38g, yield: 66 %).
LCMS m/z＝238.2[M+1]+ LCMS m/z＝238.2[M+1] +
第三步：115c的制备Step 3: Preparation of 115c
将115b(0.38g，1.60mmol)溶于甲苯(4mL)和水(0.4mL)的混合溶剂中，0℃下加入浓盐酸(1mL)，搅拌30min后缓慢加入亚硝酸钠(150mg，2.17mmol)，0-5℃反应30min，加入2mL碘化钾(0.53g，3.2mmol)的水溶液，室温反应4h。向反应体系中加入水(20mL)，用乙酸乙酯萃取(30mL×2)，有机相用饱和硫代硫酸钠溶液洗涤(20mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝91:9)，得115c(0.35g，收率：63％)。Dissolve 115b (0.38g, 1.60mmol) in a mixed solvent of toluene (4mL) and water (0.4mL), add concentrated hydrochloric acid (1mL) at 0°C, stir for 30 minutes, and then slowly add sodium nitrite (150mg, 2.17mmol) , react at 0-5°C for 30 minutes, add 2 mL of potassium iodide (0.53g, 3.2mmol) aqueous solution, and react at room temperature for 4 hours. Add water (20mL) to the reaction system, extract with ethyl acetate (30mL×2), wash the organic phase with saturated sodium thiosulfate solution (20mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is washed with silica gel Chromatographic column separation and purification (petroleum ether:ethyl acetate (v/v)=91:9) yielded 115c (0.35g, yield: 63%).
LCMS m/z＝349.0[M+1]+ LCMS m/z＝349.0[M+1] +
第四步：115d的制备Step 4: Preparation of 115d
将115c(0.35g，1.01mmol)加入到100mL单口瓶中，依次加入甲醇(4mL)、水(0.4mL)和氢氧化钾(0.21g，3.74mmol)，60℃反应5h。将反应体系冷却至室温，用1mol/L盐酸调pH至3，用乙酸乙酯萃取(30mL×2)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:1)，得粗品(0.15g)。将上述粗品(0.1g)溶于1mL乙腈中，加入二氯亚砜(55mg，0.46mmol)，60℃反应1h后，冷却至室温，加入TEA(0.2mL)，加入2-氯-4-(三氟甲基)苯胺(61mg，0.31mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝5:1)，得115d(86mg，收率：56％)。Add 115c (0.35g, 1.01mmol) into a 100mL single-neck bottle, add methanol (4mL), water (0.4mL) and potassium hydroxide (0.21g, 3.74mmol) in sequence, and react at 60°C for 5h. Cool the reaction system to room temperature, adjust the pH to 3 with 1 mol/L hydrochloric acid, extract with ethyl acetate (30 mL × 2), wash the organic phase with saturated sodium chloride aqueous solution (30 mL × 2), dry over anhydrous sodium sulfate, and reduce Concentrate under pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:1) to obtain the crude product (0.15g). Dissolve the above crude product (0.1g) in 1mL acetonitrile, add thionyl chloride (55mg, 0.46mmol), react at 60°C for 1 hour, cool to room temperature, add TEA (0.2mL), add 2-chloro-4-( Trifluoromethyl)aniline (61 mg, 0.31 mmol), reacted at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=5:1) to obtain 115d (86 mg, yield: 56%).
第五步：化合物115的制备Step 5: Preparation of Compound 115
将115d(130mg，0.26mmol)加入到反应瓶中，依次加入干燥DMF(3mL)、上述粗品中间体1(130mg)和TEA(79mg，0.78mmol)，置换氮气三次，加入PdCl2(PPh3)2(36mg，0.051mmol)和CuI(9mg，0.047mmol)，氮气氛围下55℃反应3h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(150mL)，用乙酸乙酯萃取(30mL×2)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:2)，得化合物115(21mg，收率：11％)。Add 115d (130 mg, 0.26 mmol) into the reaction flask, add dry DMF (3 mL), the above crude intermediate 1 (130 mg) and TEA (79 mg, 0.78 mmol) in sequence, replace nitrogen three times, and add PdCl 2 (PPh 3 ) 2 (36 mg, 0.051 mmol) and CuI (9 mg, 0.047 mmol), reacted at 55°C for 3 hours under nitrogen atmosphere. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (150mL), extract with ethyl acetate (30mL×2), wash the organic phase with saturated aqueous sodium chloride solution (30mL×2), and dry over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=1:2) to obtain compound 115 (21 mg, yield: 11%).
1H NMR(400MHz,CDCl3)δ8.59(d,1H),8.04–7.82(m,2H),7.68(d,1H),7.60–7.44(m,2H),7.37–7.25(m,2H),7.21–7.11(m,1H),6.87–6.77(m,1H),6.57(dd,1H),4.98–4.87(m,1H),4.44–4.32(m,2H),4.17–4.04(m,2H),3.93–3.76(m,1H),3.04–2.54(m,7H),2.36–2.19(m,1H),2.19 –2.08(m,1H),2.06–1.90(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.59(d,1H),8.04–7.82(m,2H),7.68(d,1H),7.60–7.44(m,2H),7.37–7.25(m,2H) ),7.21–7.11(m,1H),6.87–6.77(m,1H),6.57(dd,1H),4.98–4.87(m,1H),4.44–4.32(m,2H),4.17–4.04(m ,2H),3.93–3.76(m,1H),3.04–2.54(m,7H),2.36–2.19(m,1H),2.19 –2.08(m,1H),2.06–1.90(m,1H).
实施例116：化合物116的制备
Example 116: Preparation of Compound 116
以化合物116a为原料，参考实施例102的合成方法得到化合物116。Using compound 116a as a raw material, compound 116 was obtained by referring to the synthesis method of Example 102.
1H NMR(400MHz,CDCl3)δ9.43(s,1H),8.45(d,1H),8.22–8.08(m,2H),7.96–7.82(m,3H),7.73–7.35(m,7H),6.93–6.87(m,1H),6.64(dd,1H),4.98–4.87(m,1H),4.87–4.62(m,3H),4.35–4.21(m,2H),2.94–2.62(m,3H),2.18–2.02(m,7H),1.68–1.52(m,1H),1.07–0.96(m,2H),0.66–0.56(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.43(s,1H),8.45(d,1H),8.22–8.08(m,2H),7.96–7.82(m,3H),7.73–7.35(m,7H ),6.93–6.87(m,1H),6.64(dd,1H),4.98–4.87(m,1H),4.87–4.62(m,3H),4.35–4.21(m,2H),2.94–2.62(m ,3H),2.18–2.02(m,7H),1.68–1.52(m,1H),1.07–0.96(m,2H),0.66–0.56(m,2H).
实施例117：化合物117的制备
Example 117: Preparation of Compound 117
第一步：117b的制备Step One: Preparation of 117b
将117a(5.3g，39.79mmol)溶解于100mL DCM中，加入TEA(6.1g，60.3mmol)，0℃缓慢滴加三氟乙酸酐(10.5g，50mmol)，室温反应2h。将反应体系减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到117b(9.0g，收率：99％)。Dissolve 117a (5.3g, 39.79mmol) in 100mL DCM, add TEA (6.1g, 60.3mmol), slowly add trifluoroacetic anhydride (10.5g, 50mmol) at 0°C, and react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 117b (9.0 g, yield: 99%).
第二步：117c的制备Step 2: Preparation of 117c
将117b(9.0g，39.27mmol)溶解于100mL乙腈中，0℃加入NBS(7.7g，43.26mmol)，室温反应12h。将反应体系减压浓缩，加入200mL乙酸乙酯和200mL纯化水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到117c(12.0g，收率：99％)。 Dissolve 117b (9.0g, 39.27mmol) in 100 mL acetonitrile, add NBS (7.7g, 43.26mmol) at 0°C, and react at room temperature for 12 hours. The reaction system was concentrated under reduced pressure, and 200 mL of ethyl acetate and 200 mL of purified water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 117c (12.0 g, yield: 99%).
以化合物117c为原料，参考实施例102得到化合物117(120mg)。Using compound 117c as a raw material, compound 117 (120 mg) was obtained with reference to Example 102.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.48–8.34(m,2H),7.94–7.84(m,2H),7.67(d,1H),7.48(dd,1H),7.39–7.20(m,3H),6.91–6.83(m,1H),6.60(dd,1H),5.00–4.87(m,1H),4.55–4.40(m,2H),4.24–4.05(m,3H),3.10–2.98(m,2H),2.98–2.65(m,5H),2.23–2.07(m,3H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.90(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.22(s,1H),8.48–8.34(m,2H),7.94–7.84(m,2H),7.67(d,1H),7.48(dd,1H), 7.39–7.20(m,3H),6.91–6.83(m,1H),6.60(dd,1H),5.00–4.87(m,1H),4.55–4.40(m,2H),4.24–4.05(m,3H ),3.10–2.98(m,2H),2.98–2.65(m,5H),2.23–2.07(m,3H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.90(m ,2H),0.60–0.52(m,2H).
实施例118：化合物118的制备
Example 118: Preparation of Compound 118
第一步：118b的制备Step One: Preparation of 118b
将118a(0.4g，1.51mmol)(合成方法见WO2022187588)溶解于20mL DCM中，加入戴斯-马丁氧化剂(0.77g，1.82mmol)，室温反应10min。向反应体系中加入10mL水和20mL二氯甲烷，搅拌2min后，分液，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到118b(0.3g，收率：76％)。Dissolve 118a (0.4g, 1.51mmol) (see WO2022187588 for synthesis method) in 20mL DCM, add Dess-Martin oxidant (0.77g, 1.82mmol), and react at room temperature for 10 minutes. Add 10 mL water and 20 mL methylene chloride to the reaction system, stir for 2 minutes, separate the liquids, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=3:1), 118b (0.3g, yield: 76%) was obtained.
第二步：118c的制备Step 2: Preparation of 118c
将118b(0.15g，0.57mmol)、(1-重氮基-2-氧代丙基)膦酸二甲酯(0.17g，0.88mmol)和碳酸钾(0.16g，1.16mmol)加入到5mL甲醇中，30℃反应12h。将反应体系减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到118c(0.05g，收率：34％)。118b (0.15g, 0.57mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.17g, 0.88mmol) and potassium carbonate (0.16g, 1.16mmol) were added to 5 mL of methanol Medium, react at 30°C for 12 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain 118c (0.05 g, yield: 34%).
第三步：118d的制备Step 3: Preparation of 118d
将118c(0.05g，0.19mmol)溶于5mL乙醇中，加入5mL氢氧化钠(0.023g，0.58mmol)的水溶液，80℃反应2h。将反应体系冷却至室温，减压浓缩，加入5mL水，用1mol/L盐酸调pH至2，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得到粗品(0.02g)。将上述粗品(0.02g)溶于5mL乙腈中，加入3-氨基-2,6-哌啶二酮盐酸盐(0.014g，0.085mmol)和N,N'-羰基二咪唑(0.028g，0.17mmol)，90℃反应3h。将反应体系冷却至室温，减压浓缩，粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝50:1)，得到118d(0.01g，收率：37％)。Dissolve 118c (0.05g, 0.19mmol) in 5mL of ethanol, add 5mL of sodium hydroxide (0.023g, 0.58mmol) aqueous solution, and react at 80°C for 2 hours. Cool the reaction system to room temperature, concentrate under reduced pressure, add 5 mL of water, adjust the pH to 2 with 1 mol/L hydrochloric acid, extract with ethyl acetate (20 mL × 3), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Crude product (0.02g). Dissolve the above crude product (0.02g) in 5mL acetonitrile, add 3-amino-2,6-piperidinedione hydrochloride (0.014g, 0.085mmol) and N,N'-carbonyldiimidazole (0.028g, 0.17 mmol), react at 90°C for 3 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50:1) to obtain 118d (0.01 g, yield: 37%).
LCMS m/z＝323.4[M+1]+ LCMS m/z＝323.4[M+1] +
第四步：化合物118的制备Step 4: Preparation of Compound 118
将118d(0.01g，0.031mmol)、2c(0.15g，0.032mmol)、PdCl2(PPh3)2(2.2mg，0.003mmol)、CuI(1.2mg，0.0063mmol)和TEA(0.019g，0.19mmol)加入到反应瓶中，氮气氛围下55℃反应2h。将反应体系冷却至室温，加入到20mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用prep-TLC制备纯化(二氯甲烷:石油醚:乙酸乙酯(v/v)＝2:2:1)，得到化合物118(6mg，收率：29％)。118d (0.01g, 0.031mmol), 2c (0.15g, 0.032mmol), PdCl 2 (PPh 3 ) 2 (2.2mg, 0.003mmol), CuI (1.2mg, 0.0063mmol) and TEA (0.019g, 0.19mmol) ) was added into the reaction bottle, and the reaction was carried out at 55°C for 2 hours under a nitrogen atmosphere. The reaction system was cooled to room temperature and added to 20 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by prep-TLC (dichloro Methane:petroleum ether:ethyl acetate (v/v)=2:2:1) to obtain compound 118 (6 mg, yield: 29%).
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.54(d,1H),8.05(s,1H),7.80–7.62(m,4H),7.61–7.55(m,1H),7.54–7.45(m,1H),5.00–4.92(m,1H),3.60–3.47(m,1H),3.46–3.32(m,2H),3.25– 3.13(m,2H),3.12–2.97(m,2H),2.97–2.65(m,5H),2.30–1.95(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.71(s,1H),8.54(d,1H),8.05(s,1H),7.80–7.62(m,4H),7.61–7.55(m,1H), 7.54–7.45(m,1H),5.00–4.92(m,1H),3.60–3.47(m,1H),3.46–3.32(m,2H),3.25– 3.13(m,2H),3.12–2.97(m,2H),2.97–2.65(m,5H),2.30–1.95(m,3H).
实施例119：化合物119的制备
Example 119: Preparation of Compound 119
以化合物118d和68c为原料，参考实施例118的合成方法得到化合物119。Using compounds 118d and 68c as raw materials, compound 119 was obtained by referring to the synthesis method of Example 118.
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.37(d,1H),7.99(s,1H),7.77(s,1H),7.74–7.65(m,3H),7.49(dd,1H),7.41–7.34(m,1H),5.02–4.90(m,1H),3.60–3.47(m,1H),3.47–3.33(m,2H),3.26–3.12(m,2H),2.97–2.65(m,3H),2.20–2.09(m,1H),1.94(s,6H),1.54–1.44(m,1H),1.03–0.92(m,2H),0.63–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.09(s,1H),8.37(d,1H),7.99(s,1H),7.77(s,1H),7.74–7.65(m,3H),7.49( dd,1H),7.41–7.34(m,1H),5.02–4.90(m,1H),3.60–3.47(m,1H),3.47–3.33(m,2H),3.26–3.12(m,2H), 2.97–2.65(m,3H),2.20–2.09(m,1H),1.94(s,6H),1.54–1.44(m,1H),1.03–0.92(m,2H),0.63–0.52(m,2H ).
实施例120与121：化合物120与121三氟乙酸盐的制备
Examples 120 and 121: Preparation of trifluoroacetate salts of compounds 120 and 121
第一步：120b-1与120b-2的制备Step One: Preparation of 120b-1 and 120b-2
向反应瓶中分别加入120a(0.32g,1.51mmol)(合成方法参考WO2022199503)、28B(0.52g,1.46mmol)、碳酸铯(0.98g,3.01mmol)和6mL乙腈，60℃反应4h。将反应体系冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20)，得到粗品120b-1与120b-2的混合物(0.50g)。Add 120a (0.32g, 1.51mmol) (refer to WO2022199503 for synthesis method), 28B (0.52g, 1.46mmol), cesium carbonate (0.98g, 3.01mmol) and 6mL acetonitrile respectively into the reaction bottle, and react at 60°C for 4 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain crude products 120b-1 and 120b-2. Mixture (0.50g).
第二步：化合物120与121三氟乙酸盐的制备Step 2: Preparation of trifluoroacetate salts of compounds 120 and 121
在氮气氛围下，向反应瓶中分别加入上述粗品120b-1与120b-2的混合物(0.50g)、粗品中间体1(0.52g,1.53mmol)、PdCl2(PPh3)2(72mg,0.10mmol)、CuI(39mg,0.20mmol)和DIPEA(0.40g,3.09mmol)，加入10mL DMF，60℃反应5h。将反应体系冷却至室温，加入到水(40mL)中，过滤，将滤饼过Pre-HPLC(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是SunFire@Prep C18，5μm，内径×长度＝19mm×250mm)。制备方法：粗品的DMSO溶液用0.45μm滤膜过滤，制备成样品液。流动相体系：水(含0.1％三氟乙酸)/乙腈。梯度洗脱方法：乙腈由50％梯度洗脱90％，冻干分别得到化合物120的三氟乙酸盐(洗脱时间16.90min)(5mg)与化合物121的三氟乙酸盐(洗脱时间16.02min)(10mg)。Under a nitrogen atmosphere, the mixture of the above crude products 120b-1 and 120b-2 (0.50g), crude intermediate 1 (0.52g, 1.53mmol), and PdCl 2 (PPh 3 ) 2 (72mg, 0.10 mmol), CuI (39 mg, 0.20 mmol) and DIPEA (0.40 g, 3.09 mmol), add 10 mL DMF, and react at 60°C for 5 hours. Cool the reaction system to room temperature, add it to water (40 mL), filter, and pass the filter cake through Pre-HPLC (instrument and preparation column: Waters 2767 is used to prepare the liquid phase. The preparation column model is SunFire@Prep C18, 5 μm, inner diameter × Length=19mm×250mm). Preparation method: Filter the crude DMSO solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. Gradient elution method: acetonitrile gradient elutes from 50% to 90%, and freeze-drying to obtain the trifluoroacetate salt of compound 120 (elution time 16.90 min) (5 mg) and the trifluoroacetate salt of compound 121 (elution time 16.90 min). 16.02min)(10mg).
化合物120三氟乙酸盐的表征数据：Characterization data of compound 120 trifluoroacetate:
LCMS m/z＝697.1[M+1]+ LCMS m/z＝697.1[M+1] +
化合物121三氟乙酸盐的表征数据：Characterization data of compound 121 trifluoroacetate:
LCMS m/z＝697.1[M+1]+ LCMS m/z＝697.1[M+1] +
将化合物121三氟乙酸盐用氨水游离得化合物121的游离碱。The free base of compound 121 is obtained by dissociating the trifluoroacetate salt of compound 121 with ammonia water.
化合物121游离碱核磁：Compound 121 free base NMR:
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.53(d,1H),8.03(s,1H),7.69(d,1H),7.62–7.57(m,1H),7.55–7.44(m,2H),6.83(d,1H),6.58(dd,1H),4.99–4.90(m,1H),4.47–4.34(m,2H),4.22–4.10(m,2H),3.97–3.85(m,1H),3.12–2.97(m,2H),2.96–2.66(m,5H),2.30–2.02(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.62(s,1H),8.53(d,1H),8.03(s,1H),7.69(d,1H),7.62–7.57(m,1H),7.55– 7.44(m,2H),6.83(d,1H),6.58(dd,1H),4.99–4.90(m,1H),4.47–4.34(m,2H),4.22–4.10(m,2H),3.97– 3.85(m,1H),3.12–2.97(m,2H),2.96–2.66(m,5H),2.30–2.02(m,3H).
实施例122与123：化合物122与123三氟乙酸盐的制备
Examples 122 and 123: Preparation of trifluoroacetate salts of compounds 122 and 123
第一步：122a-1与122a-2的制备Step 1: Preparation of 122a-1 and 122a-2
向反应瓶中分别加入120a(0.31g,1.46mmol)(合成方法参考WO2022199503)、53B(0.46g,1.50mmol)、碳酸铯(0.94g,2.89mmol)和6mL乙腈，60℃反应4h。将反应体系冷却至室温，过滤，将滤液减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20)，得到粗品122a-1与122a-2的混合物(0.52g)。Add 120a (0.31g, 1.46mmol) (refer to WO2022199503 for synthesis method), 53B (0.46g, 1.50mmol), cesium carbonate (0.94g, 2.89mmol) and 6mL acetonitrile respectively into the reaction bottle, and react at 60°C for 4 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain crude products 122a-1 and 122a-2. Mixture (0.52g).
第二步：化合物122与123三氟乙酸盐的制备Step 2: Preparation of trifluoroacetate salts of compounds 122 and 123
在氮气氛围下，向反应瓶中分别加入上述粗品122a-1与122a-2的混合物(0.52g)、粗品中间体1(0.61g)、PdCl2(PPh3)2(84mg,0.12mmol)、CuI(46mg,0.24mmol)和DIPEA(0.47g,3.64mmol)，加入10mL DMF，60℃反应5h。将反应体系冷却至室温，加入到水(40mL)中，过滤，将滤饼过Pre-HPLC(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是SunFire@Prep C18，5μm，内径×长度＝19mm×250mm)。制备方法：粗品的DMSO溶液用0.45μm滤膜过滤，制备成样品液。流动相体系：水(含0.1％三氟乙酸)/乙腈。梯度洗脱方法：乙腈由50％梯度洗脱70％，冻干分别得到化合物122的三氟乙酸盐(洗脱时间15.88min)(6mg)与化合物123的三氟乙酸盐(洗脱时间14.58min)(20mg)。Under a nitrogen atmosphere, the mixture of the above-mentioned crude products 122a-1 and 122a-2 (0.52g), crude intermediate 1 (0.61g), PdCl 2 (PPh 3 ) 2 (84 mg, 0.12 mmol), were added to the reaction bottle respectively. CuI (46 mg, 0.24 mmol) and DIPEA (0.47 g, 3.64 mmol) were added with 10 mL DMF and reacted at 60°C for 5 hours. Cool the reaction system to room temperature, add it to water (40 mL), filter, and pass the filter cake through Pre-HPLC (instrument and preparation column: Waters 2767 is used to prepare the liquid phase. The preparation column model is SunFire@Prep C18, 5 μm, inner diameter × Length=19mm×250mm). Preparation method: Filter the crude DMSO solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. Gradient elution method: Gradient elution of acetonitrile from 50% to 70%, and freeze-drying to obtain the trifluoroacetate salt of compound 122 (elution time 15.88 min) (6 mg) and the trifluoroacetate salt of compound 123 (elution time 15.88 min). 14.58min)(20mg).
化合物122三氟乙酸盐的表征数据：Characterization data of compound 122 trifluoroacetate:
LCMS m/z＝648.2[M+1]+、 LCMS m/z＝648.2[M+1] +,
化合物123的三氟乙酸盐表征数据：Characterization data of the trifluoroacetate salt of compound 123:
LCMS m/z＝648.2[M+1]+ LCMS m/z＝648.2[M+1] +
将化合物123三氟乙酸盐用氨水游离得化合物123的游离碱。The free base of compound 123 is obtained by dissociating the trifluoroacetate salt of compound 123 with ammonia water.
化合物123游离碱核磁：Compound 123 free base NMR:
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.37(d,1H),8.12(s,1H),7.69(d,1H),7.58(d,1H),7.49(dd,1H),7.40–7.36(m,1H),6.88–6.80(m,1H),6.58(dd,1H),5.00–4.91(m,1H),4.46–4.35(m,2H),4.17–4.06(m,2H),3.95–3.81(m,1H),2.96–2.66(m,3H),2.20–2.07(m,1H),1.94(s,6H),1.58–1.45(m,1H),1.14–1.02(m,2H),0.65–0.56(m,2H) 1 H NMR (400MHz, CDCl 3 ) δ9.06(s,1H),8.37(d,1H),8.12(s,1H),7.69(d,1H),7.58(d,1H),7.49(dd, 1H),7.40–7.36(m,1H),6.88–6.80(m,1H),6.58(dd,1H),5.00–4.91(m,1H),4.46–4.35(m,2H),4.17–4.06( m,2H),3.95–3.81(m,1H),2.96–2.66(m,3H),2.20–2.07(m,1H),1.94(s,6H),1.58–1.45(m,1H),1.14– 1.02(m,2H),0.65–0.56(m,2H)
实施例124：化合物124的制备
Example 124: Preparation of Compound 124
第一步：124b的制备Step One: Preparation of 124b
将124a(1.0g，4.11mmol)与124A(0.88g，4.50mmol)溶于40mL DCM中，加入TCFH(1.72g，6.14mmol)与NMI(1.34g，16.32mmol)，室温反应16h。向反应体系中加入50mL水，用200mL DCM萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到124b(1.3g，收率：75％)。Dissolve 124a (1.0g, 4.11mmol) and 124A (0.88g, 4.50mmol) in 40mL DCM, add TCFH (1.72g, 6.14mmol) and NMI (1.34g, 16.32mmol), and react at room temperature for 16h. Add 50 mL of water to the reaction system, extract with 200 mL of DCM, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1), obtaining 124b (1.3g, yield: 75%).
第二步：124c的制备Step 2: Preparation of 124c
将124b(0.1g，0.24mmol)、50a(102mg，0.28mmol)、碳酸钠(76mg，0.72mmol)加入到5mL 1,4-二氧六环与1mL水中，氮气氛围下加入四三苯基膦钯(28mg，0.024mmol)，氮气氛围下100℃反应4h。将反应液冷却至室温，加入20mL水，用50mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到124c(50mg，收率：36％)。Add 124b (0.1g, 0.24mmol), 50a (102mg, 0.28mmol), and sodium carbonate (76mg, 0.72mmol) to 5mL of 1,4-dioxane and 1mL of water, and add tetrakistriphenylphosphine under nitrogen atmosphere Palladium (28 mg, 0.024 mmol), reacted at 100°C for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 20 mL of water was added, and extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate ( v/v)=5:1), 124c (50 mg, yield: 36%) was obtained.
以化合物124c为原料，参考实施例23得到化合物124(25mg)。Using compound 124c as a raw material, compound 124 (25 mg) was obtained with reference to Example 23.
1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.91(s,1H),7.75–7.58(m,6H),7.58–7.48(m,4H),7.48–7.40(m,2H),6.90–6.85(m,1H),6.62(dd,1H),4.99–4.90(m,1H),4.57–4.45(m,2H),4.17–4.02(m,3H),2.96–2.66(m,3H),2.19–2.08(m,1H),1.75(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.56(d,1H),7.91(s,1H),7.75–7.58(m,6H),7.58–7.48(m,4H),7.48–7.40(m,2H ),6.90–6.85(m,1H),6.62(dd,1H),4.99–4.90(m,1H),4.57–4.45(m,2H),4.17–4.02(m,3H),2.96–2.66(m ,3H),2.19–2.08(m,1H),1.75(s,6H).
实施例125：化合物125的制备
Example 125: Preparation of Compound 125
以65c和中间体2为原料，参考实施例19得到化合物125(10mg)。1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.00–7.90(m,2H),7.80(s,1H),7.70(s,1H),7.39(d,1H),6.91–6.79(m,3H),4.95–4.87(m,1H),4.53–4.42(m,2H),4.24–4.15(m,2H),3.85–3.73(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),1.95(s,6H),1.86–1.74(m,1H),1.53–1.42(m,1H),0.94–0.80(m,4H),0.63–0.57(m,2H),0.55–0.48(m,2H).Using 65c and intermediate 2 as raw materials, compound 125 (10 mg) was obtained with reference to Example 19. 1 H NMR (400MHz, CDCl 3 ) δ8.43(s,1H),8.00–7.90(m,2H),7.80(s,1H),7.70(s,1H),7.39(d,1H),6.91– 6.79(m,3H),4.95–4.87(m,1H),4.53–4.42(m,2H),4.24–4.15(m,2H),3.85–3.73(m,1H),2.94–2.64(m,3H ),2.18–2.08(m,1H),1.95(s,6H),1.86–1.74(m,1H),1.53–1.42(m,1H),0.94–0.80(m,4H),0.63–0.57(m ,2H),0.55–0.48(m,2H).
LCMS m/z＝663.1[M+1]+ LCMS m/z＝663.1[M+1] +
实施例126：化合物126的制备
Example 126: Preparation of Compound 126
以65b为原料，参考实施例22得到化合物126(8mg)。 Using 65b as a raw material, compound 126 (8 mg) was obtained with reference to Example 22.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),8.00(d,1H),7.96(s,1H),7.71–7.64(m,3H),6.92–6.85(m,1H),6.83–6.77(m,2H),6.55(dd,1H),4.97–4.89(m,1H),4.39–4.30(m,2H),4.10–4.02(m,2H),3.87–3.74(m,1H),3.13–3.02(m,2H),2.96–2.65(m,5H),2.30–1.96(m,3H),1.84–1.74(m,1H),1.48–1.37(m,1H),0.93–0.79(m,4H),0.63–0.57(m,2H),0.53–0.46(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.12(s,1H),8.00(d,1H),7.96(s,1H),7.71–7.64(m,3H),6.92–6.85(m,1H), 6.83–6.77(m,2H),6.55(dd,1H),4.97–4.89(m,1H),4.39–4.30(m,2H),4.10–4.02(m,2H),3.87–3.74(m,1H ),3.13–3.02(m,2H),2.96–2.65(m,5H),2.30–1.96(m,3H),1.84–1.74(m,1H),1.48–1.37(m,1H),0.93–0.79 (m,4H),0.63–0.57(m,2H),0.53–0.46(m,2H).
LCMS m/z＝657.1[M+1]+ LCMS m/z＝657.1[M+1] +
实施例127：化合物127的制备
Example 127: Preparation of Compound 127
第一步：127b的制备Step One: Preparation of 127b
向反应瓶中分别加入127a的盐酸盐(0.30g)(合成方法见WO2022187588)、溴丙炔(0.12g,1.01mmol)、DIPEA(0.46g,3.56mmol)和5mL DMF，40℃反应4h。将反应体系冷却至室温，倒入50mL水中，用乙酸乙酯萃取(50mL×2)，有机相用无水硫酸钠干燥，减压浓缩，粗品用10mL二氯甲烷/甲醇(v/v)＝5:1的混合溶剂打浆，过滤，将滤饼减压干燥，得粗品127b(70mg)。Add 127a hydrochloride (0.30g) (for synthesis method, see WO2022187588), bromopropyne (0.12g, 1.01mmol), DIPEA (0.46g, 3.56mmol) and 5mL DMF respectively into the reaction bottle, and react at 40°C for 4 hours. Cool the reaction system to room temperature, pour into 50 mL of water, extract with ethyl acetate (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Use 10 mL of dichloromethane/methanol (v/v) = Beat the mixture with a 5:1 mixed solvent, filter, and dry the filter cake under reduced pressure to obtain crude product 127b (70 mg).
LCMS m/z＝338.1[M+1]+ LCMS m/z＝338.1[M+1] +
第二步：化合物127的制备Step 2: Preparation of Compound 127
在氮气氛围下，向反应瓶中分别加入上述粗品127b(70mg)、68c(88mg,0.21mmol)、PdCl2(PPh3)2(15mg,0.021mmol)、CuI(8mg,0.042mmol)和DIPEA(81mg,0.63mmol)，加入5mL DMF，60℃反应5h。将反应体系冷却至室温，加入到50mL水中，过滤，将滤饼用二氯甲烷/甲醇(v/v)＝2:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:2)，所得粗品再用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物127(2mg，收率：2％)。Under a nitrogen atmosphere, the above crude products 127b (70mg), 68c (88mg, 0.21mmol), PdCl 2 (PPh 3 ) 2 (15mg, 0.021mmol), CuI (8mg, 0.042mmol) and DIPEA ( 81 mg, 0.63 mmol), add 5 mL DMF, and react at 60°C for 5 hours. Cool the reaction system to room temperature, add it to 50 mL of water, filter, dissolve the filter cake with a mixed solvent of dichloromethane/methanol (v/v) = 2:1, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel for the crude product Chromatography column separation and purification (petroleum ether/ethyl acetate (v/v)=1:2), and the crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1) to obtain Compound 127 (2 mg, yield: 2%).
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.36(d,1H),8.10(s,1H),7.83–7.77(m,1H),7.73–7.67(m,3H),7.53–7.45(m,1H),7.40–7.34(m,1H),5.00–4.92(m,1H),4.22(s,4H),3.85(s,2H),2.97–2.67(m,3H),2.20–2.10(m,1H),1.95(s,6H),1.54–1.44(m,1H),1.00–0.92(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.09(s,1H),8.36(d,1H),8.10(s,1H),7.83–7.77(m,1H),7.73–7.67(m,3H), 7.53–7.45(m,1H),7.40–7.34(m,1H),5.00–4.92(m,1H),4.22(s,4H),3.85(s,2H),2.97–2.67(m,3H), 2.20–2.10(m,1H),1.95(s,6H),1.54–1.44(m,1H),1.00–0.92(m,2H),0.60–0.52(m,2H).
LCMS m/z＝630.2[M+1]+ LCMS m/z＝630.2[M+1] +
实施例128：化合物128的制备
Example 128: Preparation of Compound 128
以128b为原料，参考实施例19得到化合物128(110mg)。Using 128b as a raw material, compound 128 (110 mg) was obtained with reference to Example 19.
1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.17(d,1H),7.95(s,1H),7.82–7.74(m,2H),7.67(d,1H),7.24–7.19(m,1H),7.11(dd,1H),6.84–6.78(m,1H),6.55(dd,1H),4.97–4.88(m,1H),4.40– 4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.94–2.57(m,3H),2.46(d,2H),2.18–2.07(m,1H),1.94(s,6H),0.97–0.84(m,1H),0.54–0.45(m,2H),0.20–0.12(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.64(s,1H),8.17(d,1H),7.95(s,1H),7.82–7.74(m,2H),7.67(d,1H),7.24– 7.19(m,1H),7.11(dd,1H),6.84–6.78(m,1H),6.55(dd,1H),4.97–4.88(m,1H),4.40– 4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.94–2.57(m,3H),2.46(d,2H),2.18–2.07(m,1H), 1.94(s,6H),0.97–0.84(m,1H),0.54–0.45(m,2H),0.20–0.12(m,2H).
LCMS m/z＝653.1[M+1]+ LCMS m/z＝653.1[M+1] +
实施例129：化合物129的制备
Example 129: Preparation of Compound 129
以化合物89g和50a为原料，参考实施例124得到化合物129(36mg)。Using compounds 89g and 50a as raw materials, compound 129 (36 mg) was obtained with reference to Example 124.
1H NMR(400MHz,CDCl3)δ9.95(s,1H),8.81(s,1H),8.44(d,1H),8.02–7.86(m,2H),7.74–7.67(m,1H),7.66–7.54(m,3H),7.54–7.44(m,3H),7.42–7.37(m,1H),6.92–6.84(m,1H),6.62(dd,1H),5.00–4.90(m,1H),4.58–4.45(m,2H),4.18–4.02(m,3H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.85(s,6H),1.80–1.70(m,1H),1.13–1.04(m,2H),0.70–0.63(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.95(s,1H),8.81(s,1H),8.44(d,1H),8.02–7.86(m,2H),7.74–7.67(m,1H), 7.66–7.54(m,3H),7.54–7.44(m,3H),7.42–7.37(m,1H),6.92–6.84(m,1H),6.62(dd,1H),5.00–4.90(m,1H ),4.58–4.45(m,2H),4.18–4.02(m,3H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.85(s,6H),1.80–1.70(m ,1H),1.13–1.04(m,2H),0.70–0.63(m,2H).
LCMS m/z＝693.1[M+1]+ LCMS m/z＝693.1[M+1] +
实施例130：化合物130的制备
Example 130: Preparation of Compound 130
以化合物68c为原料，参考实施例124得到化合物130(48mg)。Using compound 68c as a raw material, compound 130 (48 mg) was obtained with reference to Example 124.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.41(d,1H),7.98–7.88(m,3H),7.69(d,1H),7.53–7.45(m,3H),7.41–7.33(m,3H),6.90–6.84(m,1H),6.62(dd,1H),5.00–4.87(m,1H),4.55–4.42(m,2H),4.17–3.99(m,3H),2.98–2.65(m,3H),2.22–2.08(m,1H),2.03(s,6H),1.58–1.47(m,1H),1.00–0.90(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.22(s,1H),8.41(d,1H),7.98–7.88(m,3H),7.69(d,1H),7.53–7.45(m,3H), 7.41–7.33(m,3H),6.90–6.84(m,1H),6.62(dd,1H),5.00–4.87(m,1H),4.55–4.42(m,2H),4.17–3.99(m,3H ),2.98–2.65(m,3H),2.22–2.08(m,1H),2.03(s,6H),1.58–1.47(m,1H),1.00–0.90(m,2H),0.60–0.52(m ,2H).
实施例131：化合物131的制备
Example 131: Preparation of Compound 131
以化合物131a为原料，参考实施例110的合成方法得到化合物131。Using compound 131a as a raw material, compound 131 was obtained by referring to the synthesis method of Example 110.
化合物131的核磁数据： NMR data of compound 131:
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.41(d,1H),8.18–8.11(m,2H),7.98(s,1H),7.70(d,1H),7.49(dd,1H),7.38–7.34(m,1H),7.06–6.96(m,2H),6.87(d,1H),6.62(dd,1H),4.99–4.91(m,1H),4.52–4.43(m,2H),4.10–3.93(m,3H),2.96–2.67(m,3H),2.19–2.09(m,1H),2.04(s,6H),1.57–1.47(m,1H),1.01–0.92(m,2H),0.60–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.20(s,1H),8.41(d,1H),8.18–8.11(m,2H),7.98(s,1H),7.70(d,1H),7.49( dd,1H),7.38–7.34(m,1H),7.06–6.96(m,2H),6.87(d,1H),6.62(dd,1H),4.99–4.91(m,1H),4.52–4.43( m,2H),4.10–3.93(m,3H),2.96–2.67(m,3H),2.19–2.09(m,1H),2.04(s,6H),1.57–1.47(m,1H),1.01– 0.92(m,2H),0.60–0.52(m,2H).
实施例132：化合物132的制备
Example 132: Preparation of Compound 132
以化合物132a为原料，参考实施例110的合成方法得到化合物132。Using compound 132a as a raw material, compound 132 was obtained by referring to the synthesis method of Example 110.
化合物132的核磁数据：NMR data of compound 132:
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.41(d,1H),8.07(s,1H),8.02(s,1H),7.97(s,1H),7.69(d,1H),7.50(dd,1H),7.40–7.35(m,1H),7.35–7.27(m,1H),7.21–7.13(m,1H),6.87(d,1H),6.62(dd,1H),4.99–4.90(m,1H),4.56–4.46(m,2H),4.38–4.25(m,1H),4.18–4.08(m,2H),2.96–2.66(m,3H),2.18–2.09(m,1H),2.03(s,6H),1.59–1.48(m,1H),1.00–0.92(m,2H),0.60–0.53(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.20(s,1H),8.41(d,1H),8.07(s,1H),8.02(s,1H),7.97(s,1H),7.69(d, 1H),7.50(dd,1H),7.40–7.35(m,1H),7.35–7.27(m,1H),7.21–7.13(m,1H),6.87(d,1H),6.62(dd,1H) ,4.99–4.90(m,1H),4.56–4.46(m,2H),4.38–4.25(m,1H),4.18–4.08(m,2H),2.96–2.66(m,3H),2.18–2.09( m,1H),2.03(s,6H),1.59–1.48(m,1H),1.00–0.92(m,2H),0.60–0.53(m,2H).
实施例133：化合物133的制备
Example 133: Preparation of Compound 133
化合物133以化合物127b和2c为原料，参照实施例127的合成方法得到。Compound 133 was obtained by referring to the synthesis method of Example 127 using compounds 127b and 2c as raw materials.
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.53(d,1H),7.97(s,1H),7.77(s,1H),7.73–7.67(m,3H),7.59–7.56(m,1H),7.53–7.46(m,1H),5.01–4.91(m,1H),4.24(s,4H),3.86(s,2H),3.13–2.99(m,2H),2.96–2.65(m,5H),2.30–1.98(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.71(s,1H),8.53(d,1H),7.97(s,1H),7.77(s,1H),7.73–7.67(m,3H),7.59– 7.56(m,1H),7.53–7.46(m,1H),5.01–4.91(m,1H),4.24(s,4H),3.86(s,2H),3.13–2.99(m,2H),2.96– 2.65(m,5H),2.30–1.98(m,3H).
实施例134：化合物134的制备
Example 134: Preparation of Compound 134
化合物134以80c和66j为原料，参照实施例66的合成方法得到。 Compound 134 was obtained by referring to the synthesis method of Example 66 using 80c and 66j as raw materials.
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.12(d,1H),7.82–7.65(m,4H),7.04–6.99(m,1H),6.94(dd,1H),6.46(dd,1H),6.34–6.26(m,1H),5.34–5.17(m,2H),4.73(t,1H),4.33–4.22(m,2H),4.03–3.93(m,2H),3.83–3.70(m,1H),3.00–2.86(m,1H),2.71–2.56(m,1H),2.30–2.12(m,2H),1.93(s,6H),1.87–1.75(m,1H),0.99–0.89(m,2H),0.67–0.56(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.62(s,1H),8.12(d,1H),7.82–7.65(m,4H),7.04–6.99(m,1H),6.94(dd,1H), 6.46(dd,1H),6.34–6.26(m,1H),5.34–5.17(m,2H),4.73(t,1H),4.33–4.22(m,2H),4.03–3.93(m,2H), 3.83–3.70(m,1H),3.00–2.86(m,1H),2.71–2.56(m,1H),2.30–2.12(m,2H),1.93(s,6H),1.87–1.75(m,1H ),0.99–0.89(m,2H),0.67–0.56(m,2H).
实施例135：化合物135三氟乙酸盐的制备
Example 135: Preparation of compound 135 trifluoroacetate salt
化合物135以化合物23e的对甲苯磺酸盐和2A为原料，参照实施例23的合成方法得到。Compound 135 was obtained using the p-toluenesulfonate salt of compound 23e and 2A as raw materials, and was obtained by referring to the synthesis method of Example 23.
1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.32(d,1H),8.08(s,1H),7.79(s,2H),7.45(s,1H),7.42–7.31(m,2H),6.84(d,1H),4.98–4.85(m,1H),4.55–4.40(m,2H),4.27–4.13(m,2H),3.85–3.72(m,1H),3.06(s,1H),2.97–2.65(m,3H),2.20–2.06(m,1H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.96(s,1H),8.32(d,1H),8.08(s,1H),7.79(s,2H),7.45(s,1H),7.42–7.31( m,2H),6.84(d,1H),4.98–4.85(m,1H),4.55–4.40(m,2H),4.27–4.13(m,2H),3.85–3.72(m,1H),3.06( s,1H),2.97–2.65(m,3H),2.20–2.06(m,1H),1.94(s,6H).
实施例136：化合物136的制备
Example 136: Preparation of Compound 136
第一步：136b的制备Step 1: Preparation of 136b
将136a(2.0g，5.01mmol)(合成方法见WO2022187588)溶于5mL DCM中，加入4mol/L盐酸乙酸乙酯溶液(50mL)，室温反应3h。将反应体系减压浓缩，残留物用30mL二氯甲烷和5mL甲醇溶解，加入碳酸氢钾调pH至7，过滤，将滤液减压浓缩，得到粗品136b(1.4g)。Dissolve 136a (2.0g, 5.01mmol) (see WO2022187588 for synthesis method) in 5mL DCM, add 4mol/L hydrochloric acid ethyl acetate solution (50mL), and react at room temperature for 3h. The reaction system was concentrated under reduced pressure, the residue was dissolved in 30 mL of methylene chloride and 5 mL of methanol, potassium bicarbonate was added to adjust the pH to 7, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 136b (1.4 g).
LCMS m/z＝300.3[M+1]+ LCMS m/z＝300.3[M+1] +
第二步：136c的制备Step 2: Preparation of 136c
将2c(2.0g，4.26mmol)溶于30mL DMSO中，依次加入氮杂环丁-3-基甲醇的盐酸盐(790mg，6.39mmol)、CuI(160mg，0.84mmol)、L-脯氨酸(200mg，1.74mmol)和碳酸钾(1.77g，12.81mmol)，氮气氛围下90℃反应16h。将反应液冷却至室温，加入150mL水和50mL乙酸乙酯，水相用50mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1-0:1)，得136c(300mg，收率：16％)。Dissolve 2c (2.0g, 4.26mmol) in 30mL DMSO, and add azetidin-3-ylmethanol hydrochloride (790mg, 6.39mmol), CuI (160mg, 0.84mmol), and L-proline in sequence (200mg, 1.74mmol) and potassium carbonate (1.77g, 12.81mmol), react at 90°C for 16h under nitrogen atmosphere. The reaction solution was cooled to room temperature, 150 mL of water and 50 mL of ethyl acetate were added, the water phase was extracted with 50 mL of ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/acetic acid Ethyl ester (v/v) = 1:1-0:1) to obtain 136c (300 mg, yield: 16%).
LCMS m/z＝429.1[M+1]+ LCMS m/z＝429.1[M+1] +
第三步：136d的制备Step 3: Preparation of 136d
将136c(60mg，0.14mmol)溶于15mL DMSO中，加入IBX(180mg，0.64mmol)，50℃反应4h。将反应体系冷却至室温，加入15mL饱和碳酸氢钠水溶液，室温搅拌10min后，加入40mL水和40mL乙酸乙酯，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，得到粗品136d(70mg)。 Dissolve 136c (60 mg, 0.14 mmol) in 15 mL DMSO, add IBX (180 mg, 0.64 mmol), and react at 50°C for 4 hours. Cool the reaction system to room temperature, add 15 mL of saturated aqueous sodium bicarbonate solution, stir for 10 min at room temperature, add 40 mL of water and 40 mL of ethyl acetate, wash the organic phase with 20 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Crude product 136d (70 mg) was obtained.
第四步：化合物136的制备Step 4: Preparation of Compound 136
将上述粗品136b(63mg)和上述粗品136d(70mg)溶于10mL DCM和2mL DMF中，加入1mL醋酸，40℃反应16h后，分批加入三乙酰氧基硼氢化钠(89mg，0.42mmol)，室温反应2h。向反应液中加入30mL二氯甲烷和30mL饱和碳酸氢钠水溶液，有机相用30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1-0:1)，得化合物136(10mg，从化合物136c算两步收率：10％)。Dissolve the above crude product 136b (63mg) and the above crude product 136d (70mg) in 10mL DCM and 2mL DMF, add 1mL acetic acid, react at 40°C for 16h, then add sodium triacetoxyborohydride (89mg, 0.42mmol) in batches, React at room temperature for 2 hours. Add 30 mL of methylene chloride and 30 mL of saturated aqueous sodium bicarbonate solution to the reaction solution, wash the organic phase with 30 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/acetic acid). Ethyl ester (v/v) = 1:1-0:1) to obtain compound 136 (10 mg, two-step yield calculated from compound 136c: 10%).
1H NMR(400MHz,CDCl3)δ8.57(d,1H),8.52(s,1H),8.10(s,2H),7.99(s,1H),7.61–7.54(m,1H),7.54–7.46(m,1H),7.41(s,2H),5.07–4.98(m,1H),4.70–4.50(m,2H),4.00–3.80(m,2H),3.75–3.50(m,2H),3.34–3.15(m,1H),3.08–2.68(m,10H),2.30–1.95(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.57(d,1H),8.52(s,1H),8.10(s,2H),7.99(s,1H),7.61–7.54(m,1H),7.54– 7.46(m,1H),7.41(s,2H),5.07–4.98(m,1H),4.70–4.50(m,2H),4.00–3.80(m,2H),3.75–3.50(m,2H), 3.34–3.15(m,1H),3.08–2.68(m,10H),2.30–1.95(m,4H).
实施例137：化合物137的制备
Example 137: Preparation of Compound 137
化合物137以化合物137a为原料，参照实施例44的合成方法得到。Compound 137 was obtained by referring to the synthesis method of Example 44 using compound 137a as a raw material.
1H NMR(400MHz,CDCl3)δ8.72(d,1H),8.49(s,1H),7.95(s,1H),7.74–7.53(m,6H),6.89–6.80(m,1H),6.59(dd,1H),4.99–4.89(m,1H),4.48–4.36(m,2H),4.23–4.10(m,2H),4.00–3.86(m,1H),3.00–2.62(m,3H),2.20–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.72(d,1H),8.49(s,1H),7.95(s,1H),7.74–7.53(m,6H),6.89–6.80(m,1H), 6.59(dd,1H),4.99–4.89(m,1H),4.48–4.36(m,2H),4.23–4.10(m,2H),4.00–3.86(m,1H),3.00–2.62(m,3H ),2.20–2.08(m,1H).
LCMS m/z＝653.0[M+1]+ LCMS m/z＝653.0[M+1] +
实施例138：化合物138的制备
Example 138: Preparation of Compound 138
化合物138以化合物138a为原料，参照实施例44的合成方法得到。Compound 138 was obtained by referring to the synthesis method of Example 44 using compound 138a as a raw material.
1H NMR(400MHz,CDCl3)δ10.81(s,1H),8.82(d,1H),8.63(s,1H),8.28(s,1H),7.92(s,1H),7.74–7.66(m,2H),7.64–7.56(m,1H),7.56–7.46(m,1H),6.86–6.82(m,1H),6.60(dd,1H),4.99–4.89(m,1H),4.48–4.37(m,2H),4.22–4.10(m,2H),3.98–3.85(m,1H),3.00–2.63(m,3H),2.22–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ10.81(s,1H),8.82(d,1H),8.63(s,1H),8.28(s,1H),7.92(s,1H),7.74–7.66( m,2H),7.64–7.56(m,1H),7.56–7.46(m,1H),6.86–6.82(m,1H),6.60(dd,1H),4.99–4.89(m,1H),4.48– 4.37(m,2H),4.22–4.10(m,2H),3.98–3.85(m,1H),3.00–2.63(m,3H),2.22–2.08(m,1H).
LCMS m/z＝636.1[M+1]+ LCMS m/z＝636.1[M+1] +
实施例139：化合物139的制备
Example 139: Preparation of Compound 139
化合物139以化合物139a和139A为原料，参考实施例44的合成方法得到。Compound 139 was obtained by referring to the synthesis method of Example 44 using compounds 139a and 139A as raw materials.
1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.59(d,1H),7.97(s,2H),7.82(d,1H),7.72–7.56(m, 3H),7.55–7.44(m,2H),6.87–6.80(m,1H),6.58(dd,1H),4.99–4.88(m,1H),4.47–4.35(m,2H),4.18–4.07(m,2H),3.95–3.81(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.90–1.78(m,1H),1.18–1.10(m,2H),0.83–0.72(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.73(s,1H),8.59(d,1H),7.97(s,2H),7.82(d,1H),7.72–7.56(m, 3H),7.55–7.44(m,2H),6.87–6.80(m,1H),6.58(dd,1H),4.99–4.88(m,1H),4.47–4.35(m,2H),4.18–4.07( m,2H),3.95–3.81(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.90–1.78(m,1H),1.18–1.10(m,2H), 0.83–0.72(m,2H).
实施例140：化合物140的制备
Example 140: Preparation of Compound 140
第一步：140c的制备Step One: Preparation of 140c
向140b(2.0g，6.02mmol)和氢氧化锂(0.69g，28.81mmol)加入10mL水和10mL甲醇，室温反应16h。将反应液加入到50mL水中，用1mol/L盐酸调pH至2，用乙酸乙酯萃取(50mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得到粗品(1.5g)。将上述粗品(410mg)与5-(三氟甲基)吲哚啉(0.2g，1.07mmol)溶解于20mL二氯甲烷中，加入TCFH(0.45g,1.60mmol)和NMI(0.35g,4.26mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝3:1)，得到140c(450mg，收率：86％)。Add 10 mL of water and 10 mL of methanol to 140b (2.0 g, 6.02 mmol) and lithium hydroxide (0.69 g, 28.81 mmol), and react at room temperature for 16 h. The reaction solution was added to 50 mL of water, adjusted to pH 2 with 1 mol/L hydrochloric acid, extracted with ethyl acetate (50 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product (1.5 g). Dissolve the above crude product (410mg) and 5-(trifluoromethyl)indoline (0.2g, 1.07mmol) in 20mL dichloromethane, add TCFH (0.45g, 1.60mmol) and NMI (0.35g, 4.26mmol) ), react at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=3:1) to obtain 140c (450 mg, yield: 86%).
LCMS m/z＝488.0[M+1]+ LCMS m/z＝488.0[M+1] +
第二步：化合物140的制备Step 2: Preparation of Compound 140
将140c(0.20g，0.41mmol)、上述粗品中间体1(0.21g)、TEA(0.12g，1.19mmol)、CuI(8mg，0.042mmol)和PdCl2(PPh3)2(29mg，0.041mmol)加入到反应瓶中，氮气保护下加入4mL DMF，50℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:2)，得到化合物140(0.18g，收率：63％)。140c (0.20g, 0.41mmol), the above crude intermediate 1 (0.21g), TEA (0.12g, 1.19mmol), CuI (8mg, 0.042mmol) and PdCl 2 (PPh 3 ) 2 (29mg, 0.041mmol) Add it to the reaction bottle, add 4 mL DMF under nitrogen protection, and react at 50°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/petroleum ether/ Ethyl acetate (v/v)=1:2) to obtain compound 140 (0.18g, yield: 63%).
1H NMR(400MHz,CDCl3)δ8.31(d,1H),8.01(s,1H),7.66(d,1H),7.50–7.38(m,2H),7.36–7.29(m,2H),6.90–6.83(m,2H),6.81–6.77(m,1H),6.54(dd,1H),4.97–4.88(m,1H),4.48–4.16(m,5H),4.10–4.02(m,2H),3.86–3.75(m,1H),3.32–3.07(m,2H),2.95–2.63(m,3H),2.18–2.08(m,1H),1.51–1.39(m,1H),0.83–0.66(m,3H),0.66–0.56(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.31(d,1H),8.01(s,1H),7.66(d,1H),7.50–7.38(m,2H),7.36–7.29(m,2H), 6.90–6.83(m,2H),6.81–6.77(m,1H),6.54(dd,1H),4.97–4.88(m,1H),4.48–4.16(m,5H),4.10–4.02(m,2H ),3.86–3.75(m,1H),3.32–3.07(m,2H),2.95–2.63(m,3H),2.18–2.08(m,1H),1.51–1.39(m,1H),0.83–0.66 (m,3H),0.66–0.56(m,1H).
LCMS m/z＝697.1[M+1]+ LCMS m/z＝697.1[M+1] +
实施例141：化合物141的制备
Example 141: Preparation of Compound 141
第一步：141b的制备Step One: Preparation of 141b
将CuI(1.72g，9.03mmol)和KI(1.5g，9.04mmol)加入到60mL乙腈中，75℃加入亚硝酸异戊酯(1.26g，10.76mmol)，加入141a(1.5g，6.05mmol)，75℃反应2h。将反应体系冷却至 室温，加入200mL水和150mL乙酸乙酯，垫硅藻土过滤，分液，水相用乙酸乙酯萃取(60mL×3)，有机相用饱和氯化钠水溶液洗涤(80mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝35:65)，得141b(0.8g，收率：37％)。Add CuI (1.72g, 9.03mmol) and KI (1.5g, 9.04mmol) to 60mL acetonitrile, add isoamyl nitrite (1.26g, 10.76mmol) at 75°C, and add 141a (1.5g, 6.05mmol). React at 75°C for 2 hours. Cool the reaction system to At room temperature, add 200mL water and 150mL ethyl acetate, filter through diatomaceous earth, separate the liquids, extract the aqueous phase with ethyl acetate (60mL×3), wash the organic phase with saturated sodium chloride aqueous solution (80mL×2), anhydrous Dry over sodium sulfate and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=35:65) to obtain 141b (0.8g, yield: 37%).
LCMS m/z＝360.1[M+1]+ LCMS m/z＝360.1[M+1] +
第二步：141c的制备Step 2: Preparation of 141c
将141b(200mg，0.56mmol)溶于10mL二氯甲烷，加入2mL三氟乙酸，室温反应2h。将反应体系减压浓缩，加入10mL甲苯和TEA(56mg，0.55mmol)，加入141A(124mg，0.56mmol)，55℃反应16h。将反应体系冷却至室温，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝91:8)，得141c(100mg，收率：38％)。Dissolve 141b (200 mg, 0.56 mmol) in 10 mL dichloromethane, add 2 mL trifluoroacetic acid, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, 10 mL of toluene and TEA (56 mg, 0.55 mmol) were added, 141A (124 mg, 0.56 mmol) was added, and the reaction was carried out at 55°C for 16 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=91:8) to obtain 141c (100 mg, yield: 38%).
第三步：化合物141的制备Step 3: Preparation of Compound 141
化合物141以化合物141c为原料，参照实施例18的合成方法得到。Compound 141 was obtained by referring to the synthesis method of Example 18 using compound 141c as raw material.
1H NMR(400MHz,CDCl3)δ8.44(d,1H),7.96(s,1H),7.72–7.65(m,1H),7.64–7.60(m,1H),7.51(dd,1H),7.33–7.26(m,2H),7.23(s,1H),7.19–7.12(m,1H),6.82(d,1H),6.61(dd,1H),4.98–4.90(m,1H),4.68(s,2H),4.43–4.34(m,2H),4.17–4.06(m,2H),3.92–3.80(m,1H),3.80–3.73(m,2H),3.03–2.94(m,2H),2.94–2.65(m,3H),2.18–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.44(d,1H),7.96(s,1H),7.72–7.65(m,1H),7.64–7.60(m,1H),7.51(dd,1H), 7.33–7.26(m,2H),7.23(s,1H),7.19–7.12(m,1H),6.82(d,1H),6.61(dd,1H),4.98–4.90(m,1H),4.68( s,2H),4.43–4.34(m,2H),4.17–4.06(m,2H),3.92–3.80(m,1H),3.80–3.73(m,2H),3.03–2.94(m,2H), 2.94–2.65(m,3H),2.18–2.08(m,1H).
LCMS m/z＝690.2[M+1]+ LCMS m/z＝690.2[M+1] +
实施例142：化合物142的制备
Example 142: Preparation of Compound 142
化合物142以化合物142c为原料，参照实施例80的合成方法得到。Compound 142 was obtained by referring to the synthesis method of Example 80 using compound 142c as raw material.
1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.13(s,1H),8.01(d,1H),7.82–7.74(m,2H),7.67(d,1H),7.07(d,1H),6.82–6.79(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.99–2.60(m,7H),2.18–2.00(m,3H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.54(s,1H),8.13(s,1H),8.01(d,1H),7.82–7.74(m,2H),7.67(d,1H),7.07( d,1H),6.82–6.79(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88– 3.75(m,1H),2.99–2.60(m,7H),2.18–2.00(m,3H),1.94(s,6H).
LCMS m/z＝639.3[M+1]+ LCMS m/z＝639.3[M+1] +
实施例143：化合物143的制备
Example 143: Preparation of Compound 143
第一步：143b的制备Step One: Preparation of 143b
将143a(0.45g，2.0mmol)与143A(530mg,2.24mmol)溶解于20mL二氯甲烷中，加入TCFH(0.85g,3.03mmol)，加入NMI(0.67g,8.16mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝5:1)，得到143b(820mg，收率：93％)。Dissolve 143a (0.45g, 2.0mmol) and 143A (530mg, 2.24mmol) in 20mL dichloromethane, add TCFH (0.85g, 3.03mmol), add NMI (0.67g, 8.16mmol), and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=5:1) to obtain 143b (820 mg, yield: 93%).
LCMS m/z＝444.2[M+1]+ LCMS m/z＝444.2[M+1] +
第二步：化合物143的制备 Step 2: Preparation of Compound 143
将143b(0.22g，0.50mmol)、上述粗品中间体1(0.25g)、TEA(0.15g，1.48mmol)、CuI(10mg，0.053mmol)和PdCl2(PPh3)2(35mg，0.050mmol)加入到反应瓶中，氮气保护下加入4mL DMF，50℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:2)，得到化合物143(0.18g，收率：55％)。143b (0.22g, 0.50mmol), the above crude intermediate 1 (0.25g), TEA (0.15g, 1.48mmol), CuI (10mg, 0.053mmol) and PdCl 2 (PPh 3 ) 2 (35mg, 0.050mmol) Add it to the reaction bottle, add 4 mL DMF under nitrogen protection, and react at 50°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/petroleum ether/ Ethyl acetate (v/v)=1:2) to obtain compound 143 (0.18g, yield: 55%).
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.98(s,1H),7.85(d,1H),7.73(s,1H),7.70–7.60(m,2H),7.58–7.48(m,1H),7.43(s,1H),6.99–6.90(m,1H),6.86–6.77(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H),3.92–3.77(m,1H),2.95–2.63(m,3H),2.19–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.04(s,1H),7.98(s,1H),7.85(d,1H),7.73(s,1H),7.70–7.60(m,2H),7.58– 7.48(m,1H),7.43(s,1H),6.99–6.90(m,1H),6.86–6.77(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.44– 4.32(m,2H),4.17–4.05(m,2H),3.92–3.77(m,1H),2.95–2.63(m,3H),2.19–2.07(m,1H).
LCMS m/z＝653.0[M+1]+ LCMS m/z＝653.0[M+1] +
实施例144：化合物144的制备
Example 144: Preparation of Compound 144
化合物144以化合物144a为原料，参考实施例18的合成方法得到。Compound 144 was obtained by using compound 144a as a raw material and referring to the synthesis method of Example 18.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.83(s,1H),7.75(s,1H),7.67(d,1H),7.58(s,1H),6.84–6.78(m,1H),6.77–6.69(m,2H),6.59(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.17–4.02(m,2H),3.88–3.75(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),2.05(s,6H),1.95(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.05(s,1H),7.83(s,1H),7.75(s,1H),7.67(d,1H),7.58(s,1H),6.84–6.78( m,1H),6.77–6.69(m,2H),6.59(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.17–4.02(m,2H),3.88– 3.75(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),2.05(s,6H),1.95(s,6H).
LCMS m/z＝611.2[M+1]+ LCMS m/z＝611.2[M+1] +
实施例145：化合物145的制备
Example 145: Preparation of Compound 145
化合物145以化合物145a为原料，参考实施例18的合成方法得到。Compound 145 was obtained by using compound 145a as a raw material and referring to the synthesis method of Example 18.
1H NMR(400MHz,CDCl3)δ8.14(s,1H),8.09(s,1H),7.80(s,1H),7.76(s,1H),7.70(d,1H),7.67(d,1H),7.00–6.95(m,1H),6.95–6.91(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.97–4.89(m,1H),4.40–4.31(m,2H),4.13–4.02(m,2H),3.87–3.75(m,1H),2.95–2.65(m,3H),2.26(s,3H),2.17–2.07(m,1H),2.06–2.02(m,3H),1.94(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.14(s,1H),8.09(s,1H),7.80(s,1H),7.76(s,1H),7.70(d,1H),7.67(d, 1H),7.00–6.95(m,1H),6.95–6.91(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.97–4.89(m,1H),4.40–4.31( m,2H),4.13–4.02(m,2H),3.87–3.75(m,1H),2.95–2.65(m,3H),2.26(s,3H),2.17–2.07(m,1H),2.06– 2.02(m,3H),1.94(s,6H).
LCMS m/z＝593.2[M+1]+ LCMS m/z＝593.2[M+1] +
实施例146：化合物146的制备
Example 146: Preparation of Compound 146
化合物146以化合物146d为原料，参考实施例110的合成方法得到。Compound 146 was obtained by using compound 146d as raw material and referring to the synthesis method of Example 110.
化合物146的核磁数据：NMR data of compound 146:
1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.65(s,1H),8.22(s,1H),8.05(d,1H),7.73–7.62(m,2H),7.62–7.46(m,5H),6.91–6.86(m,1H),6.75(dd,1H),5.11–5.02(m,1H),4.55–4.44(m,2H),4.32–4.20(m,1H),4.18–4.08(m,2H),2.95–2.80(m,1H),2.70–2.45(m,2H),2.07–1.97(m,1H),1.92(s,6H),1.68–1.58(m,1H),0.88–0.76(m,2H),0.62–0.53(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.00(s,1H),8.65(s,1H),8.22(s,1H),8.05(d,1H),7.73–7.62(m,2H), 7.62–7.46(m,5H),6.91–6.86(m,1H),6.75(dd,1H),5.11–5.02(m,1H),4.55–4.44(m,2H),4.32–4.20(m,1H ),4.18–4.08(m,2H),2.95–2.80(m,1H),2.70–2.45(m,2H),2.07–1.97(m,1H),1.92(s,6H),1.68–1.58(m ,1H),0.88–0.76(m,2H),0.62–0.53(m,2H).
实施例147：化合物147的制备
Example 147: Preparation of Compound 147
第一步：147b的制备Step One: Preparation of 147b
将147a(1.42g，4.98mmol)溶于50mL 1,4-二氧六环和10mL纯化水中，氮气氛围下依次加入环丙基硼酸(0.81g，9.43mmol)、磷酸钾(2.2g，10.36mmol)、醋酸钯(0.23g，1.02mmol)和三环己基膦(0.56g，2.0mmol)，95℃反应16h。将反应体系冷却至室温，加入80mL乙酸乙酯和50mL纯化水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝4:1)，得147b(0.8g，收率：78％)。Dissolve 147a (1.42g, 4.98mmol) in 50mL of 1,4-dioxane and 10mL of purified water, and add cyclopropylboronic acid (0.81g, 9.43mmol) and potassium phosphate (2.2g, 10.36mmol) in sequence under a nitrogen atmosphere. ), palladium acetate (0.23g, 1.02mmol) and tricyclohexylphosphine (0.56g, 2.0mmol), react at 95°C for 16h. The reaction system was cooled to room temperature, 80 mL of ethyl acetate and 50 mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 4:1), 147b (0.8g, yield: 78%) was obtained.
LCMS m/z＝208.1[M+1]+ LCMS m/z＝208.1[M+1] +
化合物147以化合物147b为原料，参考实施例18的合成方法得到。Compound 147 was obtained by using compound 147b as a raw material and referring to the synthesis method of Example 18.
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.83(s,1H),7.79–7.71(m,2H),7.67(d,1H),6.92–6.85(m,1H),6.83–6.77(m,1H),6.66–6.60(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.31(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.94–2.63(m,3H),2.17–2.04(m,1H),1.96(s,6H),1.84–1.64(m,2H),0.97–0.88(m,2H),0.84–0.75(m,2H),0.66–0.58(m,2H),0.55–0.47(m, 2H). 1 H NMR (400MHz, CDCl 3 ) δ8.18(s,1H),7.83(s,1H),7.79–7.71(m,2H),7.67(d,1H),6.92–6.85(m,1H), 6.83–6.77(m,1H),6.66–6.60(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.31(m,2H),4.13–4.02(m,2H ),3.88–3.75(m,1H),2.94–2.63(m,3H),2.17–2.04(m,1H),1.96(s,6H),1.84–1.64(m,2H),0.97–0.88(m ,2H),0.84–0.75(m,2H),0.66–0.58(m,2H),0.55–0.47(m, 2H).
LCMS m/z＝679.1[M+1]+ LCMS m/z＝679.1[M+1] +
实施例148：化合物148的制备
Example 148: Preparation of Compound 148
化合物148以化合物148a为原料，参考实施例147的合成方法得到。Compound 148 was obtained by using compound 148a as a raw material and referring to the synthesis method of Example 147.
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.93(s,1H),7.84(s,1H),7.74(s,1H),7.68(d,1H),7.15(s,2H),6.85–6.77(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),2.96–2.66(m,3H),2.19–2.07(m,1H),1.97(s,6H),1.77–1.65(m,2H),0.94–0.78(m,4H),0.58–0.49(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.25(s,1H),7.93(s,1H),7.84(s,1H),7.74(s,1H),7.68(d,1H),7.15(s, 2H),6.85–6.77(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.12–4.02(m,2H),3.88–3.75( m,1H),2.96–2.66(m,3H),2.19–2.07(m,1H),1.97(s,6H),1.77–1.65(m,2H),0.94–0.78(m,4H),0.58– 0.49(m,4H).
LCMS m/z＝670.7[M+1]+ LCMS m/z＝670.7[M+1] +
实施例149：化合物149的制备
Example 149: Preparation of Compound 149
第一步：149b的制备Step One: Preparation of 149b
将149a(2g，6.06mmol)溶于100mL 1,4-二氧六环和20mL水的混合溶剂中，加入环丙基硼酸(4.7g，54.7mmol)、磷酸钾(19g，89.51mmol)、Pd(OAc)2(410mg，1.83mmol)和三环己基膦(512mg，1.83mmol)，氮气氛围下100℃反应16h。将反应体系冷却至室温，加入水(120mL)和乙酸乙酯(160mL)，垫硅藻土过滤，将滤液分液，水相用乙酸乙酯萃取(100mL×2)，有机相用饱和氯化钠水溶液洗涤(100mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝87:13)，得149b(700mg，收率：54％)。Dissolve 149a (2g, 6.06mmol) in a mixed solvent of 100mL 1,4-dioxane and 20mL water, add cyclopropylboronic acid (4.7g, 54.7mmol), potassium phosphate (19g, 89.51mmol), and Pd (OAc) 2 (410 mg, 1.83 mmol) and tricyclohexylphosphine (512 mg, 1.83 mmol) were reacted at 100°C for 16 hours under nitrogen atmosphere. Cool the reaction system to room temperature, add water (120 mL) and ethyl acetate (160 mL), filter through diatomaceous earth, separate the filtrate, extract the aqueous phase with ethyl acetate (100 mL × 2), and use saturated chlorine to remove the organic phase. Wash with sodium aqueous solution (100 mL rate: 54%).
LCMS m/z＝214.3[M+1]+ LCMS m/z＝214.3[M+1] +
化合物149以化合物149b为原料，参照实施例18的合成方法得到。Compound 149 was obtained by referring to the synthesis method of Example 18 using compound 149b as raw material.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.83(s,1H),7.75–7.70(m,2H),7.67(d,1H),6.84–6.78(m,1H),6.60–6.50(m,3H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.97(s,6H),1.83–1.72(m,1H),1.72–1.60(m,2H),0.93–0.83(m,2H),0.80–0.70(m,4H),0.62–0.55(m,2H),0.54–0.45(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.91(s,1H),7.83(s,1H),7.75–7.70(m,2H),7.67(d,1H),6.84–6.78(m,1H), 6.60–6.50(m,3H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m ,3H),2.18–2.08(m,1H),1.97(s,6H),1.83–1.72(m,1H),1.72–1.60(m,2H),0.93–0.83(m,2H),0.80–0.70 (m,4H),0.62–0.55(m,2H),0.54–0.45(m,4H).
LCMS m/z＝685.3[M+1]+ LCMS m/z＝685.3[M+1] +
实施例150：化合物150的制备
Example 150: Preparation of Compound 150
化合物150以化合物150a为原料，参照实施例18的合成方法得到。Compound 150 was obtained by using compound 150a as a raw material and referring to the synthesis method of Example 18.
1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.08–7.99(m,2H),7.77(s,2H),7.67(d,1H),6.86–6.78(m,2H),6.72(dd,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),2.95–2.63(m,3H),2.18–2.05(m,1H),1.92(s,6H),1.88–1.75(m,1H),0.96–0.88(m,2H),0.66–0.58(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.58(s,1H),8.08–7.99(m,2H),7.77(s,2H),7.67(d,1H),6.86–6.78(m,2H), 6.72(dd,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H), 2.95–2.63(m,3H),2.18–2.05(m,1H),1.92(s,6H),1.88–1.75(m,1H),0.96–0.88(m,2H),0.66–0.58(m,2H ).
LCMS m/z＝623.3[M+1]+ LCMS m/z＝623.3[M+1] +
实施例151：化合物151的制备
Example 151: Preparation of Compound 151
第一步：151b的制备Step One: Preparation of 151b
将151a(1.0g，5.11mmol)溶于20mL DMF中，加入3-氟-5-碘苯胺(1.2g，5.06mmol)和N,N'-羰基二咪唑(0.91g，5.61mmol)，80℃反应12h。将反应体系冷却到室温，加入到100mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用20mL乙醚打浆，过滤，将滤饼真空干燥，得到粗品151b(1.0g)。Dissolve 151a (1.0g, 5.11mmol) in 20mL DMF, add 3-fluoro-5-iodoaniline (1.2g, 5.06mmol) and N,N'-carbonyldiimidazole (0.91g, 5.61mmol), 80℃ Reaction 12h. Cool the reaction system to room temperature, add it to 100 mL of ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution (50 mL The cake was vacuum dried to obtain crude product 151b (1.0 g).
第二步：化合物151的制备Step 2: Preparation of Compound 151
将上述粗品151b(0.11g)和上述粗品中间体1(0.12g)、TEA(0.14g，1.38mmol)、CuI(8.8mg，0.046mmol)和PdCl2(PPh3)2(16mg，0.023mmol)加入到反应瓶中，氮气保护下加入2mL DMF，55℃反应3h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-10:7)，得到化合物151(0.05g，从化合物151a算两步收率：13％)。The above crude product 151b (0.11g) and the above crude intermediate 1 (0.12g), TEA (0.14g, 1.38mmol), CuI (8.8mg, 0.046mmol) and PdCl 2 (PPh 3 ) 2 (16mg, 0.023mmol) Add it to the reaction bottle, add 2 mL DMF under nitrogen protection, and react at 55°C for 3 hours. Cool the reaction solution to room temperature, add it to 50 mL of ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution (20 mL /ethyl acetate (v/v)=1:0-10:7) to obtain compound 151 (0.05g, two-step yield calculated from compound 151a: 13%).
1H NMR(400MHz,CDCl3)δ8.38(d,1H),8.14(s,1H),7.67–7.56(m,2H),7.50(d,1H),7.44–7.27(m,2H),7.23–7.12(m,2H),6.88–6.80(m,1H),6.76–6.68(m,1H),6.54–6.46(m,1H),5.02–4.90(m,1H),4.40–4.27(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.97–2.65(m,3H),2.21–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.38(d,1H),8.14(s,1H),7.67–7.56(m,2H),7.50(d,1H),7.44–7.27(m,2H), 7.23–7.12(m,2H),6.88–6.80(m,1H),6.76–6.68(m,1H),6.54–6.46(m,1H),5.02–4.90(m,1H),4.40–4.27(m ,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.97–2.65(m,3H),2.21–2.08(m,1H).
实施例152：化合物152的制备
Example 152: Preparation of Compound 152
化合物152以化合物152b+152A为原料，参照实施例18的合成方法得到。Compound 152 was obtained by using compound 152b+152A as raw materials and referring to the synthesis method of Example 18.
1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.95(s,1H),7.90(d,1H),7.80(s,1H),7.72–7.64(m,2H),6.98–6.92(m,1H),6.81(d,1H),6.74(dd,1H),6.55(dd,1H),4.98–4.87(m,1H),4.40–4.30(m,2H),4.12–4.02(m,2H),3.88–3.73(m,1H),2.95–2.62(m,3H),2.18–2.07(m,1H),1.95(s,6H),1.91–1.80(m,1H),1.49–1.39(m,1H),0.95–0.77(m,4H),0.73–0.62(m,2H),0.55–0.44(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.51(s,1H),7.95(s,1H),7.90(d,1H),7.80(s,1H),7.72–7.64(m,2H),6.98– 6.92(m,1H),6.81(d,1H),6.74(dd,1H),6.55(dd,1H),4.98–4.87(m,1H),4.40–4.30(m,2H),4.12–4.02( m,2H),3.88–3.73(m,1H),2.95–2.62(m,3H),2.18–2.07(m,1H),1.95(s,6H),1.91–1.80(m,1H),1.49– 1.39(m,1H),0.95–0.77(m,4H),0.73–0.62(m,2H),0.55–0.44(m,2H).
LCMS m/z＝645.3[M+1]+ LCMS m/z＝645.3[M+1] +
实施例153：化合物153的制备
Example 153: Preparation of Compound 153
化合物153以化合物74b和中间体2为原料，参照实施例44的合成方法得到。Compound 153 was obtained by referring to the synthesis method of Example 44 using compound 74b and intermediate 2 as raw materials.
1H NMR(400MHz,CDCl3)δ8.69(d,1H),8.43(s,1H),7.93(s,1H),7.84(s,1H),7.80(s,1H),7.71(s,1H),7.67–7.57(m,2H),7.41(d,1H),6.87(d,1H),4.98–4.85(m,1H),4.58–4.46(m,2H),4.34–4.20(m,2H),3.94–3.77(m,1H),2.97–2.65(m,3H),2.21–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.69(d,1H),8.43(s,1H),7.93(s,1H),7.84(s,1H),7.80(s,1H),7.71(s, 1H),7.67–7.57(m,2H),7.41(d,1H),6.87(d,1H),4.98–4.85(m,1H),4.58–4.46(m,2H),4.34–4.20(m, 2H),3.94–3.77(m,1H),2.97–2.65(m,3H),2.21–2.07(m,1H).
实施例154：化合物154的制备
Example 154: Preparation of Compound 154
化合物154以化合物154a为原料，参照实施例147的合成方法得到。Compound 154 was obtained by using compound 154a as a raw material and referring to the synthesis method of Example 147.
1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.98(s,1H),7.83(s,1H),7.75(s,1H),7.67(d,1H),7.55–7.49(m,1H),7.23–7.18(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.06(m,1H),1.97(s,6H),1.83–1.70(m,1H),0.96–0.84(m,2H),0.62–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.38(s,1H),7.98(s,1H),7.83(s,1H),7.75(s,1H),7.67(d,1H),7.55–7.49( m,1H),7.23–7.18(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13– 4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.06(m,1H),1.97(s,6H),1.83–1.70(m,1H), 0.96–0.84(m,2H),0.62–0.52(m,2H).
实施例156：化合物156的制备
Example 156: Preparation of Compound 156
第一步：156b的制备Step 1: Preparation of 156b
将156A(140mg，0.53mmol)溶于15mL干燥二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺(100mg，0.75mmol)，室温反应1.5h后，加入TEA(151mg，1.49mmol)和156a(94mg，0.5mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝9:1)，得156b(100mg，收率：46％)。Dissolve 156A (140mg, 0.53mmol) in 15mL dry dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (100mg, 0.75mmol), react at room temperature for 1.5h, then add TEA (151mg, 1.49mmol) and 156a (94mg, 0.5mmol), reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 9:1) to obtain 156b (100 mg, yield: 46%).
LCMS m/z＝436.1[M+1]+ LCMS m/z＝436.1[M+1] +
化合物156以化合物156b为原料，参照实施例44的合成方法得到。Compound 156 was obtained by referring to the synthesis method of Example 44 using compound 156b as a raw material.
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.40–7.40(m,7H),6.92–6.84(m,1H),6.73(dd,1H),5.11–4.98(m,1H),4.47–4.35(m,2H),4.15–3.90(m,5H),3.23–3.09(m,2H),2.96–2.79(m,1H),2.70–2.45(m,2H),2.07–1.96(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.05(s,1H),8.40–7.40(m,7H),6.92–6.84(m,1H),6.73(dd,1H),5.11–4.98(m ,1H),4.47–4.35(m,2H),4.15–3.90(m,5H),3.23–3.09(m,2H),2.96–2.79(m,1H),2.70–2.45(m,2H),2.07 –1.96(m,1H).
LCMS m/z＝645.6[M+1]+ LCMS m/z＝645.6[M+1] +
实施例157：化合物157的制备
Example 157: Preparation of Compound 157
化合物157以化合物157a和65b为原料，参照实施例44的合成方法得到。Compound 157 was obtained by referring to the synthesis method of Example 44 using compounds 157a and 65b as raw materials.
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.15(d,1H),7.90(s,1H),7.72–7.57(m,3H),7.57–7.50(m,1H),7.02–6.92(m,2H),6.87–6.81(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.48–4.36(m,2H),4.20–4.12(m,2H),3.97–3.86(m,1H),2.96–2.64(m,3H),2.18–2.08(m,1H),1.93–1.77(m,2H),1.07–0.98(m,2H),0.98–0.90(m,2H),0.76–0.70(m,2H),0.70–0.63(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.40(s,1H),8.15(d,1H),7.90(s,1H),7.72–7.57(m,3H),7.57–7.50(m,1H), 7.02–6.92(m,2H),6.87–6.81(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.48–4.36(m,2H),4.20–4.12(m,2H ),3.97–3.86(m,1H),2.96–2.64(m,3H),2.18–2.08(m,1H),1.93–1.77(m,2H),1.07–0.98(m,2H),0.98–0.90 (m,2H),0.76–0.70(m,2H),0.70–0.63(m,2H).
实施例158：化合物158的制备
Example 158: Preparation of Compound 158
化合物158以化合物158a和65b为原料，参照实施例44的合成方法得到。Compound 158 was obtained by referring to the synthesis method of Example 44 using compounds 158a and 65b as raw materials.
1H NMR(400MHz,CDCl3)δ10.62(s,1H),8.57(d,1H),8.35–8.26(m,2H),7.94(s,1H),7.69(d,1H),7.47–7.41(m,1H),7.02–6.89(m,2H),6.88–6.81(m,1H),6.59(dd,1H),4.98–4.90(m,1H),4.47–4.36(m,2H),4.20–4.10(m,2H),3.97–3.83(m,1H),2.96–2.66(m,3H),2.18–2.08(m,1H),1.95–1.81(m,2H),1.12–1.03(m,2H),0.98–0.82(m,2H),0.75–0.63(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ10.62(s,1H),8.57(d,1H),8.35–8.26(m,2H),7.94(s,1H),7.69(d,1H),7.47– 7.41(m,1H),7.02–6.89(m,2H),6.88–6.81(m,1H),6.59(dd,1H),4.98–4.90(m,1H),4.47–4.36(m,2H), 4.20–4.10(m,2H),3.97–3.83(m,1H),2.96–2.66(m,3H),2.18–2.08(m,1H),1.95–1.81(m,2H),1.12–1.03(m ,2H),0.98–0.82(m,2H),0.75–0.63(m,4H).
实施例159：化合物159的制备
Example 159: Preparation of Compound 159
第一步：159b的制备Step One: Preparation of 159b
将159a(1.00g，7.51mmol)溶于10mL乙腈中，冷却至0℃，加入NCS(2.01g，15.05mmol)，40℃反应5h。将反应液冷却至室温，加入90mL乙酸乙酯、100mL水和20mL 10％硫代硫酸钠水溶液，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-2:1)，得到159b(0.22g，收率：15％)。Dissolve 159a (1.00g, 7.51mmol) in 10mL acetonitrile, cool to 0°C, add NCS (2.01g, 15.05mmol), and react at 40°C for 5 hours. The reaction solution was cooled to room temperature, 90 mL of ethyl acetate, 100 mL of water and 20 mL of 10% sodium thiosulfate aqueous solution were added. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/acetic acid). Ethyl ester (v/v) = 10:1-2:1) to obtain 159b (0.22g, yield: 15%).
LCMS m/z＝202.1[M+1]+ LCMS m/z＝202.1[M+1] +
化合物159以化合物159b为原料，参照实施例18的合成方法得到。Compound 159 was obtained by referring to the synthesis method of Example 18 using compound 159b as raw material.
1H NMR(400MHz,CDCl3)δ7.94(s,2H),7.83(s,1H),7.74(s,1H),7.67(d,1H),7.23(d,1H),6.87(d,1H),6.81(d,1H),6.56(dd,1H),4.99–4.88(m,1H),4.44–4.28(m,2H),4.15–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.07(m,1H),1.96(s,6H),1.77–1.66(m,1H),0.92–0.80(m,2H),0.60–0.50(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,2H),7.83(s,1H),7.74(s,1H),7.67(d,1H),7.23(d,1H),6.87(d, 1H),6.81(d,1H),6.56(dd,1H),4.99–4.88(m,1H),4.44–4.28(m,2H),4.15–4.02(m,2H),3.88–3.75(m, 1H),2.98–2.65(m,3H),2.18–2.07(m,1H),1.96(s,6H),1.77–1.66(m,1H),0.92–0.80(m,2H),0.60–0.50( m,2H).
LCMS m/z＝673.2[M+1]+ LCMS m/z＝673.2[M+1] +
实施例160：化合物160的制备
Example 160: Preparation of Compound 160
化合物160以化合物160a为原料，参照实施例147的合成方法得到。Compound 160 was obtained by using compound 160a as a raw material and referring to the synthesis method of Example 147.
1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.97(s,1H),7.77(d,2H),7.67(d,1H),6.94–6.86(m,2H),6.84–6.78(m,1H),6.60–6.48(m,2H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.06(m,1H),1.90(s,6H),1.85–1.74(m,2H),0.96–0.82(m,4H),0.70–0.60(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.29(s,1H),7.97(s,1H),7.77(d,2H),7.67(d,1H),6.94–6.86(m,2H),6.84– 6.78(m,1H),6.60–6.48(m,2H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H ),2.95–2.65(m,3H),2.18–2.06(m,1H),1.90(s,6H),1.85–1.74(m,2H),0.96–0.82(m,4H),0.70–0.60(m ,4H).
LCMS m/z＝645.3[M+1]+ LCMS m/z＝645.3[M+1] +
实施例161：化合物161的制备
Example 161: Preparation of Compound 161
化合物161以化合物161a为原料，参考实施例160的合成方法得到。Compound 161 was obtained by using compound 161a as a raw material and referring to the synthesis method of Example 160.
1H NMR(400MHz,CDCl3)δ8.26(s,1H),7.96(s,1H),7.80–7.74(m,2H),7.67(d,1H),7.12–7.06(m,1H),7.04–7.00(m,1H),6.87(d,1H),6.83–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.32(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.24–2.05(m,3H), 1.90(s,6H),1.00–0.82(m,4H),0.70–0.55(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.26(s,1H),7.96(s,1H),7.80–7.74(m,2H),7.67(d,1H),7.12–7.06(m,1H), 7.04–7.00(m,1H),6.87(d,1H),6.83–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.32(m,2H), 4.12–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.24–2.05(m,3H), 1.90(s,6H),1.00–0.82(m,4H),0.70–0.55(m,4H).
LCMS m/z＝645.2[M+1]+ LCMS m/z＝645.2[M+1] +
实施例162：化合物162的制备
Example 162: Preparation of Compound 162
化合物162以化合物74b和66j为原料，参考实施例74的合成方法得到。Compound 162 was obtained by referring to the synthesis method of Example 74 using compounds 74b and 66j as raw materials.
1H NMR(400MHz,CDCl3)δ8.68(d,1H),8.43(s,1H),7.94–7.77(m,3H),7.74–7.68(m,1H),7.66–7.56(m,2H),6.58–6.48(m,1H),6.33(s,1H),5.66–5.35(m,2H),4.84–4.66(m,1H),4.50–4.33(m,2H),4.24–4.06(m,2H),3.97–3.77(m,1H),3.04–2.87(m,1H),2.85–2.50(m,2H),2.48–2.27(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.68(d,1H),8.43(s,1H),7.94–7.77(m,3H),7.74–7.68(m,1H),7.66–7.56(m,2H ),6.58–6.48(m,1H),6.33(s,1H),5.66–5.35(m,2H),4.84–4.66(m,1H),4.50–4.33(m,2H),4.24–4.06(m ,2H),3.97–3.77(m,1H),3.04–2.87(m,1H),2.85–2.50(m,2H),2.48–2.27(m,1H).
LCMS m/z＝655.0[M+1]+ LCMS m/z＝655.0[M+1] +
实施例163：化合物163的制备
Example 163: Preparation of Compound 163
第一步：163b的制备Step One: Preparation of 163b
将163A(1.0g，4.84mmol)溶于30mL 1,4-二氧六环和10mL水中，氮气保护下加入163a(1.01g，7.22mmol)、碳酸钾(1.07g，7.74mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.39g，0.48mmol)，86℃反应12h。将反应体系冷却到室温，加入到50mL水中，用50mL乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-10:7)，得到163b(1.0g，收率：93％)。Dissolve 163A (1.0g, 4.84mmol) in 30mL 1,4-dioxane and 10mL water, add 163a (1.01g, 7.22mmol), potassium carbonate (1.07g, 7.74mmol) and [1, 1'-Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.39g, 0.48mmol), reacted at 86°C for 12h. The reaction system was cooled to room temperature, added to 50 mL of water, and extracted three times with 50 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/ v)=1:0-10:7), 163b (1.0g, yield: 93%) was obtained.
LCMS m/z＝222.1[M+1]+ LCMS m/z＝222.1[M+1] +
化合物163以化合物163b为原料，参照实施例104的合成方法得到。Compound 163 was obtained by referring to the synthesis method of Example 104 using compound 163b as a raw material.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.20(d,1H),7.92(s,1H),7.82(s,1H),7.73(s,1H),7.67(d,1H),7.51–7.42(m,2H),7.37(dd,1H),7.27–7.23(m,1H),7.13–7.04(m,2H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.97(s,6H),1.62–1.50(m,1H),1.00–0.78(m,2H),0.64–0.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.66(s,1H),8.20(d,1H),7.92(s,1H),7.82(s,1H),7.73(s,1H),7.67(d, 1H),7.51–7.42(m,2H),7.37(dd,1H),7.27–7.23(m,1H),7.13–7.04(m,2H),6.84–6.77(m,1H),6.55(dd, 1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.18– 2.07(m,1H),1.97(s,6H),1.62–1.50(m,1H),1.00–0.78(m,2H),0.64–0.54(m,2H).
实施例164：化合物164的制备
Example 164: Preparation of Compound 164
化合物164以化合物164a(合成方法见WO2022143489)为原料，参照实施例165的合成方法得到。Compound 164 was obtained by using compound 164a (see WO2022143489 for the synthesis method) as a raw material and referring to the synthesis method of Example 165.
1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.38–8.32(m,1H),8.29–8.24(m,1H),8.23–8.18(m,1H),8.07–7.97(m,1H),7.83(s,2H),7.70–7.57(m,2H),7.49–7.40(m,1H),7.39–7.30(m,1H),6.88–6.82(m,1H),6.74–6.64(m,1H),5.12–5.02(m,1H),4.47–4.35(m,2H),4.10–3.97(m,2H),3.95–3.80(m,1H),2.99–2.80(m,1H),2.68–2.52(m,2H),2.10–2.00(m,1H),1.92(s,6H),1.77–1.65(m,1H),0.96–0.84(m,2H),0.68–0.58(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.85(s,1H),8.38–8.32(m,1H),8.29–8.24(m,1H),8.23–8.18(m,1H),8.07–7.97 (m,1H),7.83(s,2H),7.70–7.57(m,2H),7.49–7.40(m,1H),7.39–7.30(m,1H),6.88–6.82(m,1H),6.74 –6.64(m,1H),5.12–5.02(m,1H),4.47–4.35(m,2H),4.10–3.97(m,2H),3.95–3.80(m,1H),2.99–2.80(m, 1H),2.68–2.52(m,2H),2.10–2.00(m,1H),1.92(s,6H),1.77–1.65(m,1H),0.96–0.84(m,2H),0.68–0.58( m,2H).
实施例165：化合物165的制备
Example 165: Preparation of Compound 165
化合物165以化合物165a为原料，参照实施例147的合成方法得到。Compound 165 was obtained by referring to the synthesis method of Example 147 using compound 165a as a raw material.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.82(s,1H),7.73(s,1H),7.67(d,1H),7.49(s,1H),6.83–6.79(m,1H),6.72(s,2H),6.56(dd,1H),4.98–4.88(m,1H),4.42–4.31(m,2H),4.13–4.02(m,2H),3.87–3.76(m,1H),2.96–2.66(m,3H),2.18–2.07(m,1H),2.02(s,6H),1.95(s,6H),1.83–1.72(m,1H),0.92–0.84(m,2H),0.66–0.57(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,1H),7.82(s,1H),7.73(s,1H),7.67(d,1H),7.49(s,1H),6.83–6.79( m,1H),6.72(s,2H),6.56(dd,1H),4.98–4.88(m,1H),4.42–4.31(m,2H),4.13–4.02(m,2H),3.87–3.76( m,1H),2.96–2.66(m,3H),2.18–2.07(m,1H),2.02(s,6H),1.95(s,6H),1.83–1.72(m,1H),0.92–0.84( m,2H),0.66–0.57(m,2H).
LCMS m/z＝633.2[M+1]+ LCMS m/z＝633.2[M+1] +
实施例166：化合物166的制备
Example 166: Preparation of Compound 166
化合物166以化合物166a和65b为原料，参考实施例44的合成方法得到。Compound 166 was obtained by referring to the synthesis method of Example 44 using compounds 166a and 65b as raw materials.
1H NMR(400MHz,CDCl3)δ8.35(s,1H),8.11(d,1H),7.92(s,1H),7.74–7.65(m,2H),7.60–7.51(m,1H),7.34–7.26(m,1H),7.02–6.92(m,2H),6.86–6.79(m,1H),6.58(dd,1H),4.99–4.89(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H),3.94–3.80(m,1H),2.96–2.66(m,3H),2.20–2.08(m,1H),1.94–1.76(m,2H),1.08–0.98(m,2H),0.98–0.90(m,2H),0.77–0.69(m,2H),0.69–0.63 (m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.35(s,1H),8.11(d,1H),7.92(s,1H),7.74–7.65(m,2H),7.60–7.51(m,1H), 7.34–7.26(m,1H),7.02–6.92(m,2H),6.86–6.79(m,1H),6.58(dd,1H),4.99–4.89(m,1H),4.45–4.35(m,2H ),4.18–4.07(m,2H),3.94–3.80(m,1H),2.96–2.66(m,3H),2.20–2.08(m,1H),1.94–1.76(m,2H),1.08–0.98 (m,2H),0.98–0.90(m,2H),0.77–0.69(m,2H),0.69–0.63 (m,2H).
实施例167：化合物167的制备
Example 167: Preparation of Compound 167
化合物167以化合物167a和65b为原料，参照实施例44的合成方法得到。Compound 167 was obtained by referring to the synthesis method of Example 44 using compounds 167a and 65b as raw materials.
1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.09(d,1H),7.95(s,1H),7.83–7.77(m,2H),7.69(d,1H),7.61–7.55(m,1H),7.02–6.90(m,2H),6.86–6.80(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H),3.93–3.80(m,1H),2.96–2.65(m,3H),2.20–2.08(m,1H),1.92–1.76(m,2H),1.08–0.98(m,2H),0.98–0.90(m,2H),0.78–0.69(m,2H),0.69–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.33(s,1H),8.09(d,1H),7.95(s,1H),7.83–7.77(m,2H),7.69(d,1H),7.61– 7.55(m,1H),7.02–6.90(m,2H),6.86–6.80(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.45–4.35(m,2H), 4.18–4.07(m,2H),3.93–3.80(m,1H),2.96–2.65(m,3H),2.20–2.08(m,1H),1.92–1.76(m,2H),1.08–0.98(m ,2H),0.98–0.90(m,2H),0.78–0.69(m,2H),0.69–0.62(m,2H).
实施例168：化合物168的制备
Example 168: Preparation of Compound 168
化合物168以化合物168a为原料，参照实施例166的合成方法得到。Compound 168 was obtained by referring to the synthesis method of Example 166 using compound 168a as raw material.
1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.35–8.27(m,2H),8.02–7.90(m,3H),7.84–7.62(m,5H),7.41–7.34(m,1H),6.84–6.76(m,1H),6.57(dd,1H),4.98–4.88(m,1H),4.48–4.35(m,2H),4.20–4.07(m,2H),3.95–3.82(m,1H),2.95–2.63(m,3H),2.18–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.41(s,1H),8.35–8.27(m,2H),8.02–7.90(m,3H),7.84–7.62(m,5H),7.41–7.34(m ,1H),6.84–6.76(m,1H),6.57(dd,1H),4.98–4.88(m,1H),4.48–4.35(m,2H),4.20–4.07(m,2H),3.95–3.82 (m,1H),2.95–2.63(m,3H),2.18–2.07(m,1H).
LCMS m/z＝624.2[M-1]- LCMS m/z＝624.2[M-1] -
实施例169：化合物169的制备
Example 169: Preparation of Compound 169
化合物169以化合物65b为原料，参考实施例151的合成方法得到。Compound 169 was obtained by using compound 65b as raw material and referring to the synthesis method of Example 151.
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.59(d,1H),7.29(d,1H),7.25–7.19(m,1H),7.07–7.02(m,1H),6.86–6.77(m,1H),6.77–6.63(m,4H),6.57–6.40(m,2H),4.92–4.80(m,1H),4.34–4.22(m,2H),4.04–3.92(m,2H),3.79–3.62(m,1H),2.88–2.55(m,3H),2.12–2.00(m,1H),1.87–1.72(m,2H),0.94–0.80(m,4H),0.64–0.52(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.02(s,1H),7.59(d,1H),7.29(d,1H),7.25–7.19(m,1H),7.07–7.02(m,1H), 6.86–6.77(m,1H),6.77–6.63(m,4H),6.57–6.40(m,2H),4.92–4.80(m,1H),4.34–4.22(m,2H),4.04–3.92(m ,2H),3.79–3.62(m,1H),2.88–2.55(m,3H),2.12–2.00(m,1H),1.87–1.72(m,2H),0.94–0.80(m,4H),0.64 –0.52(m,4H).
实施例170：化合物170的制备
Example 170: Preparation of Compound 170
化合物170以化合物75b和中间体2为原料，参照实施例153的合成方法得到。Compound 170 was obtained by referring to the synthesis method of Example 153 using compound 75b and intermediate 2 as raw materials.
1H NMR(400MHz,CDCl3)δ11.07(s,1H),10.47(s,1H),8.02–7.97(m,1H),7.97–7.93(m,1H),7.91–7.83(m,1H),7.83–7.74(m,2H),7.69–7.59(m,2H),7.03(d,1H),5.12–5.02(m,1H),4.60–4.47(m,2H),4.28–4.17(m,2H),4.03–3.88(m,1H),2.96–2.79(m,1H),2.67–2.44(m,2H),2.10–1.95(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ11.07(s,1H),10.47(s,1H),8.02–7.97(m,1H),7.97–7.93(m,1H),7.91–7.83(m,1H) ),7.83–7.74(m,2H),7.69–7.59(m,2H),7.03(d,1H),5.12–5.02(m,1H),4.60–4.47(m,2H),4.28–4.17(m ,2H),4.03–3.88(m,1H),2.96–2.79(m,1H),2.67–2.44(m,2H),2.10–1.95(m,1H).
LCMS m/z＝669.0[M-1]- LCMS m/z＝669.0[M-1] -
实施例171：化合物171的制备
Example 171: Preparation of Compound 171
化合物171以化合物75b和66j为原料，参照实施例66的合成方法得到。Compound 171 was obtained by referring to the synthesis method of Example 66 using compounds 75b and 66j as raw materials.
1H NMR(400MHz,CDCl3)δ8.70(d,1H),8.44(s,1H),7.80–7.66(m,4H),7.66–7.52(m,2H),7.38–7.28(m,1H),6.53–6.45(m,1H),6.33(s,1H),5.34–5.20(m,2H),4.78–4.69(m,1H),4.38–4.27(m,2H),4.10–3.98(m,2H),3.90–3.75(m,1H),3.02–2.85(m,1H),2.72–2.55(m,1H),2.28–2.10(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.70(d,1H),8.44(s,1H),7.80–7.66(m,4H),7.66–7.52(m,2H),7.38–7.28(m,1H ),6.53–6.45(m,1H),6.33(s,1H),5.34–5.20(m,2H),4.78–4.69(m,1H),4.38–4.27(m,2H),4.10–3.98(m ,2H),3.90–3.75(m,1H),3.02–2.85(m,1H),2.72–2.55(m,1H),2.28–2.10(m,2H).
LCMS m/z＝639.1[M+1]+ LCMS m/z＝639.1[M+1] +
实施例172：化合物172的制备
Example 172: Preparation of Compound 172
化合物172以化合物172a为原料，参照实施例154的合成方法得到。Compound 172 was obtained by using compound 172a as a raw material and referring to the synthesis method of Example 154.
1H NMR(400MHz,CDCl3)δ8.50(s,1H),8.38(s,1H),8.03–7.95(m,1H),7.82(s,1H),7.72(s,1H),7.66(d,1H),6.94–6.83(m,1H),6.83–6.78(m,1H),6.78–6.72(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.87–3.72(m,1H),2.93–2.65(m,3H),2.17–2.07(m,1H),1.95(s,6H),1.56–1.46(m,1H),0.94–0.84(m,2H),0.58–0.49(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.50(s,1H),8.38(s,1H),8.03–7.95(m,1H),7.82(s,1H),7.72(s,1H),7.66( d,1H),6.94–6.83(m,1H),6.83–6.78(m,1H),6.78–6.72(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42– 4.30(m,2H),4.13–4.00(m,2H),3.87–3.72(m,1H),2.93–2.65(m,3H),2.17–2.07(m,1H),1.95(s,6H), 1.56–1.46(m,1H),0.94–0.84(m,2H),0.58–0.49(m,2H).
LCMS m/z＝623.2[M+1]+ LCMS m/z＝623.2[M+1] +
实施例173：化合物173的制备
Example 173: Preparation of Compound 173
化合物173以化合物173a(合成方法见WO2021173917)和65b为原料，参考实施例44的合成方法得到。Compound 173 was obtained by using compound 173a (see WO2021173917 for the synthesis method) and 65b as raw materials, and referring to the synthesis method of Example 44.
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.12(d,1H),7.96(s,1H),7.68(d,1H),7.58(d,1H),7.53(d,1H),6.99–6.92(m,2H),6.82(d,1H),6.57(dd,1H),4.98–4.89(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H),3.91–3.77(m,1H),2.98–2.64(m,3H),2.18–2.08(m,1H),1.92–1.76(m,2H),1.10–1.00(m,2H),0.99–0.82(m,2H),0.76–0.69(m,2H),0.69–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.31(s,1H),8.12(d,1H),7.96(s,1H),7.68(d,1H),7.58(d,1H),7.53(d, 1H),6.99–6.92(m,2H),6.82(d,1H),6.57(dd,1H),4.98–4.89(m,1H),4.44–4.32(m,2H),4.17–4.05(m, 2H),3.91–3.77(m,1H),2.98–2.64(m,3H),2.18–2.08(m,1H),1.92–1.76(m,2H),1.10–1.00(m,2H),0.99– 0.82(m,2H),0.76–0.69(m,2H),0.69–0.62(m,2H).
实施例174：化合物174的制备
Example 174: Preparation of Compound 174
化合物174以化合物174b为原料，参照实施例154的合成方法得到。Compound 174 was obtained by referring to the synthesis method of Example 154 using compound 174b as a raw material.
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.06(s,1H),7.95(d,1H),7.80(s,1H),7.74–7.63(m,2H),7.03–6.95(m,1H),6.92–6.84(m,1H),6.80(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.42–4.30(m,2H),4.12–4.01(m,2H),3.87–3.75(m,1H),2.95–2.66(m,3H),2.25(s,3H),2.18–2.06(m,1H),1.95(s,6H),1.55–1.40(m,1H),0.89–0.79(m,2H),0.56–0.46(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.43(s,1H),8.06(s,1H),7.95(d,1H),7.80(s,1H),7.74–7.63(m,2H),7.03– 6.95(m,1H),6.92–6.84(m,1H),6.80(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.42–4.30(m,2H),4.12– 4.01(m,2H),3.87–3.75(m,1H),2.95–2.66(m,3H),2.25(s,3H),2.18–2.06(m,1H),1.95(s,6H),1.55– 1.40(m,1H),0.89–0.79(m,2H),0.56–0.46(m,2H).
LCMS m/z＝619.2[M+1]+ LCMS m/z＝619.2[M+1] +
实施例175：化合物175的制备
Example 175: Preparation of Compound 175
化合物175以化合物65b和81f为原料，参照实施例81的合成方法得到。Compound 175 was obtained by referring to the synthesis method of Example 81 using compounds 65b and 81f as raw materials.
1H NMR(400MHz,CDCl3)δ7.99(d,1H),7.93(s,1H),7.76–7.73(m,1H),7.68(d,1H),7.64–7.55(m,2H),7.52(s,1H),6.96(d,1H),6.83(d,1H),6.72(dd,1H),6.58(dd,1H),4.99–4.89(m,1H),4.44–4.35(m,2H),4.17–4.06(m,2H),3.95–3.82(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.93–1.80(m,1H),1.72(s,6H),1.30–1.15(m,1H),0.97–0.80(m,2H),0.73–0.65(m,2H),0.53–0.43(m,2H),0.37–0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.99(d,1H),7.93(s,1H),7.76–7.73(m,1H),7.68(d,1H),7.64–7.55(m,2H), 7.52(s,1H),6.96(d,1H),6.83(d,1H),6.72(dd,1H),6.58(dd,1H),4.99–4.89(m,1H),4.44–4.35(m, 2H),4.17–4.06(m,2H),3.95–3.82(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.93–1.80(m,1H),1.72( s,6H),1.30–1.15(m,1H),0.97–0.80(m,2H),0.73–0.65(m,2H),0.53–0.43(m,2H),0.37–0.28(m,2H).
LCMS m/z＝723.3[M+1]+ LCMS m/z＝723.3[M+1] +
实施例176：化合物176的制备
Example 176: Preparation of Compound 176
化合物176以化合物65c和66j为原料，参照实施例66的合成方法得到。Compound 176 was obtained by referring to the synthesis method of Example 66 using compounds 65c and 66j as raw materials.
1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.99–7.88(m,2H),7.79(s,1H),7.73–7.67(m,2H),6.87(dd,1H),6.83–6.77(m,1H),6.45(dd,1H),6.33–6.27(m,1H),5.32–5.18(m,2H),4.76–4.69(m,1H),4.33–4.22(m,2H),4.02–3.92(m,2H),3.83–3.70(m,1H),2.99–2.85(m,1H),2.70–2.55(m,1H),2.24–2.12(m,2H),1.94(s,6H),1.86–1.74(m,1H),1.53–1.41(m,1H),0.92–0.80(m,4H),0.64–0.56(m,2H),0.54–0.46(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.43(s,1H),7.99–7.88(m,2H),7.79(s,1H),7.73–7.67(m,2H),6.87(dd,1H), 6.83–6.77(m,1H),6.45(dd,1H),6.33–6.27(m,1H),5.32–5.18(m,2H),4.76–4.69(m,1H),4.33–4.22(m,2H ),4.02–3.92(m,2H),3.83–3.70(m,1H),2.99–2.85(m,1H),2.70–2.55(m,1H),2.24–2.12(m,2H),1.94(s ,6H),1.86–1.74(m,1H),1.53–1.41(m,1H),0.92–0.80(m,4H),0.64–0.56(m,2H),0.54–0.46(m,2H).
LCMS m/z＝631.7[M+1]+ LCMS m/z＝631.7[M+1] +
实施例177：化合物177的制备
Example 177: Preparation of Compound 177
化合物177以化合物177a为原料，参照实施例174的合成方法得到。Compound 177 was obtained by referring to the synthesis method of Example 174 using compound 177a as a raw material.
1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.05(d,1H),7.99(s,1H),7.82–7.73(m,2H),7.67(d,1H),7.16(d,1H),6.80(d,1H),6.74(dd,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.32(m,2H),4.12–4.02(m,2H),3.87–3.75(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),1.94(s,6H),1.90–1.80(m,1H),0.98–0.90(m,2H),0.72–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.67(s,1H),8.05(d,1H),7.99(s,1H),7.82–7.73(m,2H),7.67(d,1H),7.16( d,1H),6.80(d,1H),6.74(dd,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.32(m,2H),4.12–4.02(m, 2H),3.87–3.75(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),1.94(s,6H),1.90–1.80(m,1H),0.98–0.90( m,2H),0.72–0.62(m,2H).
实施例178：化合物178的制备
Example 178: Preparation of Compound 178
化合物178以化合物178a为原料，参照实施例177的合成方法得到。Compound 178 was obtained by using compound 178a as a raw material and referring to the synthesis method of Example 177.
1H NMR(400MHz,CDCl3)δ8.08–8.00(m,1H),7.90(s,1H),7.84(s,1H),7.74(s,1H),7.67(d,1H),7.22(dd,1H),7.10(t,1H),6.94–6.86(m,1H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.31(m,2H),4.12–4.03(m,2H),3.88–3.74(m,1H),2.98–2.64(m,3H),2.18–2.07(m,1H),1.98(s,6H),1.80–1.68(m,1H),0.88–0.78(m,2H),0.58–0.49(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.08–8.00(m,1H),7.90(s,1H),7.84(s,1H),7.74(s,1H),7.67(d,1H),7.22( dd,1H),7.10(t,1H),6.94–6.86(m,1H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.31(m, 2H),4.12–4.03(m,2H),3.88–3.74(m,1H),2.98–2.64(m,3H),2.18–2.07(m,1H),1.98(s,6H),1.80–1.68( m,1H),0.88–0.78(m,2H),0.58–0.49(m,2H).
LCMS m/z＝639.2[M+1]+ LCMS m/z＝639.2[M+1] +
实施例179：化合物179的制备
Example 179: Preparation of Compound 179
第一步：179b的制备Step One: Preparation of 179b
将179a(2.00g，9.69mmol)溶于20mL甲苯和2mL水的混合溶剂中，加入环丙基硼酸(4.15g，48.3mmol)，2-二环己基膦-2’,6’-二甲氧基-联苯(0.79g，1.92mmol)、Pd(OAc)2(0.22g，0.98mmol)和磷酸钾(8.20g，38.63mmol)，氮气氛围下75℃反应19h后，加入环丙基硼酸(1.66 g，19.32mmol)、2-二环己基膦-2’,6’-二甲氧基-联苯(0.79g，1.92mmol)和醋酸钯(0.22g，0.98mmol)，氮气氛围下75℃反应5h。将反应体系冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到179b(0.62g，收率：37％)。Dissolve 179a (2.00g, 9.69mmol) in a mixed solvent of 20mL toluene and 2mL water, add cyclopropylboronic acid (4.15g, 48.3mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy Base-biphenyl (0.79g, 1.92mmol), Pd(OAc) 2 (0.22g, 0.98mmol) and potassium phosphate (8.20g, 38.63mmol) were reacted at 75°C for 19 hours under a nitrogen atmosphere, and then cyclopropylboronic acid ( 1.66 g, 19.32mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (0.79g, 1.92mmol) and palladium acetate (0.22g, 0.98mmol), react at 75°C under nitrogen atmosphere 5h. The reaction system was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 179b (0.62g, yield: 37%).
LCMS m/z＝174.1[M+1]+ LCMS m/z＝174.1[M+1] +
化合物179以化合物179b为原料，参照实施例80的合成方法得到。Compound 179 was obtained by referring to the synthesis method of Example 80 using compound 179b as raw material.
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.88–7.80(m,2H),7.73(s,1H),7.67(d,1H),7.08(t,1H),6.88–6.77(m,3H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.03(m,2H),3.88–3.75(m,1H),2.94–2.64(m,3H),2.18–2.05(m,1H),1.98(s,6H),1.77–1.63(m,2H),0.84–0.74(m,4H),0.56–0.47(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.18(s,1H),7.88–7.80(m,2H),7.73(s,1H),7.67(d,1H),7.08(t,1H),6.88– 6.77(m,3H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.03(m,2H),3.88–3.75(m,1H), 2.94–2.64(m,3H),2.18–2.05(m,1H),1.98(s,6H),1.77–1.63(m,2H),0.84–0.74(m,4H),0.56–0.47(m,4H ).
LCMS m/z＝645.3[M+1]+ LCMS m/z＝645.3[M+1] +
实施例180：化合物180的制备
Example 180: Preparation of Compound 180
化合物180以化合物65b和180A为原料，参照实施例44的合成方法得到。Compound 180 was obtained by referring to the synthesis method of Example 44 using compounds 65b and 180A as raw materials.
1H NMR(400MHz,CDCl3)δ8.60–8.45(m,2H),8.24–8.10(m,2H),8.02–7.92(m,2H),7.70(d,1H),7.04–6.92(m,2H),6.88–6.80(m,1H),6.60(dd,1H),5.00–4.89(m,1H),4.48–4.38(m,2H),4.28–4.18(m,2H),4.03–3.92(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.93–1.80(m,2H),1.09–1.00(m,2H),0.98–0.91(m,2H),0.78–0.63(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.60–8.45(m,2H),8.24–8.10(m,2H),8.02–7.92(m,2H),7.70(d,1H),7.04–6.92(m ,2H),6.88–6.80(m,1H),6.60(dd,1H),5.00–4.89(m,1H),4.48–4.38(m,2H),4.28–4.18(m,2H),4.03–3.92 (m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.93–1.80(m,2H),1.09–1.00(m,2H),0.98–0.91(m,2H) ,0.78–0.63(m,4H).
实施例181：化合物181的制备
Example 181: Preparation of Compound 181
第一步：181b的制备Step One: Preparation of 181b
将181a(1.35g，10.00mmol)溶解于20mL乙腈中，0℃缓慢加入NBS(2.14g,12.02mmol)，0℃搅拌1h后，室温反应2h。将反应体系减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝3:1)，得到181b(1.2g，收率：56％)。Dissolve 181a (1.35g, 10.00mmol) in 20mL acetonitrile, slowly add NBS (2.14g, 12.02mmol) at 0°C, stir for 1 hour at 0°C, and react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=3:1) to obtain 181b (1.2g, yield: 56%).
LCMS m/z＝213.9[M+1]+ LCMS m/z＝213.9[M+1] +
化合物181以化合物181b为原料，参照实施例104的合成方法得到。Compound 181 was obtained by referring to the synthesis method of Example 104 using compound 181b as raw material.
1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.04(s,1H),7.82–7.72(m,2H),7.67(d,1H),7.28(s,1H),6.81(d,1H),6.67(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.63–4.53(m,2H),4.43–4.31(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),3.01–2.65(m,5H),2.18–2.07(m,1H),1.96–1.82(m, 7H),0.90–0.82(m,2H),0.70–0.62(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.28(s,1H),8.04(s,1H),7.82–7.72(m,2H),7.67(d,1H),7.28(s,1H),6.81( d,1H),6.67(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.63–4.53(m,2H),4.43–4.31(m,2H),4.12–4.02( m,2H),3.88–3.75(m,1H),3.01–2.65(m,5H),2.18–2.07(m,1H),1.96–1.82(m, 7H),0.90–0.82(m,2H),0.70–0.62(m,2H).
实施例182：化合物182的制备
Example 182: Preparation of Compound 182
第一步：182b的制备Step 1: Preparation of 182b
将182a(0.3g，5.45mmol)溶于5mL DMSO溶剂中，加入TEA(2.21g，21.84mmol)和182A(1.96g，7.10mmol)，80℃反应3h。将反应体系冷却至室温，加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到182b(0.11g，收率：6％)。Dissolve 182a (0.3g, 5.45mmol) in 5mL DMSO solvent, add TEA (2.21g, 21.84mmol) and 182A (1.96g, 7.10mmol), and react at 80°C for 3 hours. The reaction system was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 182b (0.11g, yield: 6%).
LCMS m/z＝312.1[M+1]+ LCMS m/z＝312.1[M+1] +
第二步：化合物182的制备Step 2: Preparation of Compound 182
将182b(0.11g，0.35mmol)、2c(0.16g，0.34mmol)、TEA(0.10g，0.99mmol)、CuI(13mg，0.068mmol)和PdCl2(PPh3)2(48mg，0.068mmol)加入到反应瓶中，氮气氛围下加入5mL DMF，55℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用60mL DCM/MeOH(v/v)＝5:1溶解，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1.5)，得化合物182(32mg，收率：14％)。182b (0.11g, 0.35mmol), 2c (0.16g, 0.34mmol), TEA (0.10g, 0.99mmol), CuI (13mg, 0.068mmol) and PdCl 2 (PPh 3 ) 2 (48mg, 0.068mmol) were added To the reaction bottle, add 5 mL DMF under nitrogen atmosphere, and react at 55°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 60 mL of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and use silica gel chromatography for the crude product. Column separation and purification (petroleum ether/ethyl acetate (v/v) = 1:1.5) gave compound 182 (32 mg, yield: 14%).
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.53(d,1H),8.16(s,1H),7.77(s,1H),7.70(s,1H),7.66(d,1H),7.60–7.55(m,1H),7.53–7.46(m,1H),7.09(d,1H),6.86(dd,1H),4.99–4.74(m,2H),4.22(s,2H),3.13–2.98(m,2H),2.94–2.64(m,5H),2.30–1.98(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.69(s,1H),8.53(d,1H),8.16(s,1H),7.77(s,1H),7.70(s,1H),7.66(d, 1H),7.60–7.55(m,1H),7.53–7.46(m,1H),7.09(d,1H),6.86(dd,1H),4.99–4.74(m,2H),4.22(s,2H) ,3.13–2.98(m,2H),2.94–2.64(m,5H),2.30–1.98(m,3H).
LCMS m/z＝653.2[M+1]+ LCMS m/z＝653.2[M+1] +
实施例183：化合物183的制备
Example 183: Preparation of Compound 183
化合物183以化合物183a(合成方法见Australian Journal of Chemistry,1965,18,1351-1364)和65b为原料，参考实施例44的合成方法得到。Compound 183 was obtained by using compound 183a (for the synthesis method, see Australian Journal of Chemistry, 1965, 18, 1351-1364) and 65b as raw materials, and referring to the synthesis method of Example 44.
1H NMR(400MHz,CDCl3)δ8.45–8.33(m,1H),8.30–8.18(m,1H),8.13(s,1H),8.06(s,1H),7.93(s,1H),7.88–7.81(m,1H),7.77(s,1H),7.69(d,1H),7.63–7.53(m,2H),7.07–6.97(m,1H),6.94(s,1H),6.84(d,1H),6.59(dd,1H),4.98–4.89(m,1H),4.47–4.35(m,2H),4.22–4.11(m,2H),3.98–3.85(m,1H),2.96–2.64(m,3H),2.20–2.08(m,1H),1.94–1.70(m,2H),1.00–0.80(m,4H),0.72–0.62(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.45–8.33(m,1H),8.30–8.18(m,1H),8.13(s,1H),8.06(s,1H),7.93(s,1H), 7.88–7.81(m,1H),7.77(s,1H),7.69(d,1H),7.63–7.53(m,2H),7.07–6.97(m,1H),6.94(s,1H),6.84( d,1H),6.59(dd,1H),4.98–4.89(m,1H),4.47–4.35(m,2H),4.22–4.11(m,2H),3.98–3.85(m,1H),2.96– 2.64(m,3H),2.20–2.08(m,1H),1.94–1.70(m,2H),1.00–0.80(m,4H),0.72–0.62(m,4H).
实施例184：化合物184的制备
Example 184: Preparation of Compound 184
化合物184以化合物184a(合成方法见Australian Journal of Chemistry,1965,18,1351-1364)为原料，参考实施例183的合成方法得到。Compound 184 was obtained by using compound 184a (for the synthesis method, see Australian Journal of Chemistry, 1965, 18, 1351-1364) as raw material, and referring to the synthesis method of Example 183.
1H NMR(400MHz,CDCl3)δ8.75(d,1H),8.34–8.17(m,2H),8.04(s,1H),7.98–7.85(m,1H),7.85–7.76(m,1H),7.76–7.70(m,1H),7.68–7.48(m,5H),6.80–6.74(m,1H),6.52(dd,1H),4.92–4.81(m,1H),4.42–4.30(m,2H),4.15–4.05(m,2H),3.90–3.76(m,1H),2.90–2.55(m,3H),2.12–2.00(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.75(d,1H),8.34–8.17(m,2H),8.04(s,1H),7.98–7.85(m,1H),7.85–7.76(m,1H ),7.76–7.70(m,1H),7.68–7.48(m,5H),6.80–6.74(m,1H),6.52(dd,1H),4.92–4.81(m,1H),4.42–4.30(m ,2H),4.15–4.05(m,2H),3.90–3.76(m,1H),2.90–2.55(m,3H),2.12–2.00(m,1H).
实施例185：化合物185的制备
Example 185: Preparation of Compound 185
第一步：185b的制备Step One: Preparation of 185b
将185a(2g，7.52mmol)溶于30mL甲醇中，缓慢滴加二氯亚砜(2mL)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝92:8)，得到185b(1.9g，收率：90％)。Dissolve 185a (2g, 7.52mmol) in 30mL methanol, slowly add thionyl chloride (2mL) dropwise, and react at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 92:8) to obtain 185b (1.9 g, yield: 90%).
第二步：185c的制备Step 2: Preparation of 185c
将185b(1.9g，6.79mmol)加入到100mL单口瓶中，加入DMF(30.0mL)，加入3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(1.8g，9.93mmol)和TEA(2.1g，20.75mmol)，氮气氛围下加入PdCl2(PPh3)2(497mg，0.71mmol)和CuI(194mg，1.02mmol)，50℃反应2h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(200mL)，用乙酸乙酯萃取(150mL×3)，有机相用饱和氯化钠水溶液洗涤(200mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝67:33)，得185c(1.3g，收率：57％)。Add 185b (1.9g, 6.79mmol) into a 100mL single-neck bottle, add DMF (30.0mL), add 3-ethynyl azetidine-1-carboxylic acid tert-butyl ester (1.8g, 9.93mmol) and TEA ( 2.1g, 20.75mmol), add PdCl 2 (PPh 3 ) 2 (497mg, 0.71mmol) and CuI (194mg, 1.02mmol) under nitrogen atmosphere, and react at 50°C for 2h. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (200mL), extract with ethyl acetate (150mL×3), wash the organic phase with saturated aqueous sodium chloride solution (200mL×2), and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 67:33) to obtain 185c (1.3 g, yield: 57%).
LCMS m/z＝334.1[M+1]+ LCMS m/z＝334.1[M+1] +
第三步：185d的制备Step 3: Preparation of 185d
将185c(1.3g，3.90mmol)加入到四氢呋喃(30mL)和水(10mL)的混合溶剂中，加入一水合氢氧化锂(819mg，19.5mmol)，室温反应16h。将反应体系用0.5mol/L盐酸调pH至7，用乙酸乙酯萃取(70mL×3)，有机相用饱和氯化钠水溶液洗涤(70mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝72:28)，得粗品185d(700mg)。将上述粗品185d(130mg)加入到500mL单口瓶中，加入干燥DCM(10mL)，加入23c(62mg，0.41mmol)和TCFH(173mg，0.62mmol)，缓慢滴加N-甲基咪唑(174mg，2.12mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝67:33)，得185d(45mg，收率：24％)。 185c (1.3g, 3.90mmol) was added to a mixed solvent of tetrahydrofuran (30mL) and water (10mL), lithium hydroxide monohydrate (819mg, 19.5mmol) was added, and the reaction was carried out at room temperature for 16h. Adjust the pH of the reaction system to 7 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (70 mL × 3), wash the organic phase with saturated sodium chloride aqueous solution (70 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=72:28) to obtain crude product 185d (700 mg). Add the above crude product 185d (130 mg) into a 500 mL single-neck bottle, add dry DCM (10 mL), add 23c (62 mg, 0.41 mmol) and TCFH (173 mg, 0.62 mmol), and slowly add N-methylimidazole (174 mg, 2.12 mmol), react at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=67:33) to obtain 185d (45 mg, yield: 24%).
LCMS m/z＝453.1[M+1]+ LCMS m/z＝453.1[M+1] +
第四步：185e的对甲苯磺酸盐的制备Step 4: Preparation of 185e p-toluenesulfonate
将185d(45mg，0.1mmol)加入到500mL单口瓶中，加入乙腈(5mL)，加入对甲苯磺酸(69mg，0.4mmol)，35℃反应4h。减压浓缩，得到粗品185f的对甲苯磺酸盐(40mg)。Add 185d (45 mg, 0.1 mmol) into a 500 mL single-neck bottle, add acetonitrile (5 mL), add p-toluenesulfonic acid (69 mg, 0.4 mmol), and react at 35°C for 4 hours. Concentrate under reduced pressure to obtain crude product 185f p-toluenesulfonate (40 mg).
LCMS m/z＝353.1[M+1]+ LCMS m/z＝353.1[M+1] +
第五步：化合物185的制备Step 5: Preparation of Compound 185
将上述粗品185f的对甲苯磺酸盐(40mg)加入到25mL单口瓶中，加入干燥DMSO(5mL)，加入DIPEA(64mg，0.49mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(41mg，0.15mmol)，80℃反应2h。将反应体系冷却至室温，缓慢加入水(60mL)，用乙酸乙酯萃取(30mL×3)，有机相用饱和氯化钠水溶液洗涤(20mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝23:77)，所得粗品经Prep-HPLC制备(仪器：WATERS AUTOP制备液相；色谱柱:SunFire@PrepC18(19x250nm)；流动相A：乙腈；流动相B：水(含5mmol/L乙酸铵)；梯度洗脱：流动相A含量从25-80％；流速：17mL/min；柱温：室温；检测波长：210nm；样品用DMF溶解，用0.45μm滤头过滤，制成样品液；洗脱时间：15min，冻干得到化合物185(3mg，收率：3％)。Add the p-toluenesulfonate (40 mg) of the above crude product 185f into a 25 mL single-neck bottle, add dry DMSO (5 mL), add DIPEA (64 mg, 0.49 mmol) and 2-(2,6-dioxopiperidine-3) -base)-5-fluoroisoindoline-1,3-dione (41 mg, 0.15 mmol), react at 80°C for 2 hours. Cool the reaction system to room temperature, slowly add water (60 mL), extract with ethyl acetate (30 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 23:77), and the crude product was prepared by Prep-HPLC (instrument: WATERS AUTOP preparation liquid phase; chromatographic column: SunFire@PrepC18 (19x250nm) ; Mobile phase A: acetonitrile; mobile phase B: water (containing 5mmol/L ammonium acetate); gradient elution: mobile phase A content from 25-80%; flow rate: 17mL/min; column temperature: room temperature; detection wavelength: 210nm ; The sample was dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution; elution time: 15 min, and lyophilized to obtain compound 185 (3 mg, yield: 3%).
1H NMR(400MHz,CDCl3)δ8.50(d,1H),8.37(s,1H),7.98(s,1H),7.73–7.65(m,2H),7.62–7.53(m,2H),7.46(dd,1H),7.36–7.30(m,1H),6.84(d,1H),6.59(dd,1H),4.98–4.90(m,1H),4.48–4.35(m,2H),4.20–4.07(m,2H),3.95–3.82(m,1H),3.11(s,1H),2.96–2.65(m,3H),2.18–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.50(d,1H),8.37(s,1H),7.98(s,1H),7.73–7.65(m,2H),7.62–7.53(m,2H), 7.46(dd,1H),7.36–7.30(m,1H),6.84(d,1H),6.59(dd,1H),4.98–4.90(m,1H),4.48–4.35(m,2H),4.20– 4.07(m,2H),3.95–3.82(m,1H),3.11(s,1H),2.96–2.65(m,3H),2.18–2.08(m,1H).
LCMS m/z＝609.7[M+1]+ LCMS m/z＝609.7[M+1] +
实施例186：化合物186的制备
Example 186: Preparation of Compound 186
第一步：186b的制备Step 1: Preparation of 186b
在0℃下将70％硝酸(1.1mL)滴加到186a(5.4g，33.29mmol)的TFA(60mL)溶液中(滴加时间为30min)，0℃下反应2h。将反应体系倒入到400mL冰水中，搅拌20min，用二氯甲烷萃取(200mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝7:3)，得到186b(4.2g，收率：61％)。70% nitric acid (1.1 mL) was added dropwise to a solution of 186a (5.4 g, 33.29 mmol) in TFA (60 mL) at 0°C (dipping time was 30 min), and the reaction was carried out at 0°C for 2 h. Pour the reaction system into 400 mL ice water, stir for 20 min, extract with dichloromethane (200 mL × 3), wash the organic phase with saturated sodium chloride aqueous solution (50 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product Separate and purify using silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=7:3) to obtain 186b (4.2g, yield: 61%).
LCMS m/z＝206.1[M-1]- LCMS m/z＝206.1[M-1] -
第二步：186c的制备Step 2: Preparation of 186c
将186b(1g，4.83mmol)溶于20mL甲醇中，加入10％钯碳(200mg)，置于氢气球氛围下室温反应16h。将反应体系垫硅藻土过滤，将滤液减压浓缩，得到粗品186c(800mg)。Dissolve 186b (1g, 4.83mmol) in 20mL methanol, add 10% palladium on carbon (200mg), and react at room temperature for 16h under a hydrogen balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude product 186c (800 mg).
LCMS m/z＝178.2[M+1]+ LCMS m/z＝178.2[M+1] +
第三步：186d的制备Step 3: Preparation of 186d
将上述粗品186c(800mg)加入到甲苯(10mL)和水(10mL)的混合溶剂中，加入浓盐酸 (1.2mL)，0℃下加入亚硝酸钠(372mg，5.39mmol)，0℃下反应30min后，缓慢加入KI(1.6g，9.64mmol)的水(10mL)溶液，室温反应2h。向反应体系中加入水(100mL)，用乙酸乙酯萃取(60mL×3)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝67:33)，得186d(500mg，收率：32％)。The above crude product 186c (800 mg) was added to a mixed solvent of toluene (10 mL) and water (10 mL), and concentrated hydrochloric acid was added. (1.2 mL), add sodium nitrite (372 mg, 5.39 mmol) at 0°C, react at 0°C for 30 min, then slowly add a solution of KI (1.6 g, 9.64 mmol) in water (10 mL), and react at room temperature for 2 h. Add water (100mL) to the reaction system, extract with ethyl acetate (60mL×3), wash the organic phase with saturated aqueous sodium chloride solution (60mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is chromatographed on silica gel Column separation and purification (petroleum ether: ethyl acetate (v/v) = 67:33) gave 186d (500 mg, yield: 32%).
化合物186以化合物186d为原料，参照实施例44的合成方法得到。Compound 186 was obtained by referring to the synthesis method of Example 44 using compound 186d as raw material.
1H NMR(400MHz,CDCl3)δ8.65–8.54(m,1H),7.95(s,1H),7.88–7.78(m,1H),7.76–7.60(m,2H),7.58–7.50(m,1H),7.50–7.12(m,3H),6.82(d,1H),6.56(dd,1H),4.99–4.88(m,1H),4.45–4.32(m,2H),4.18–4.03(m,2H),3.95–3.77(m,1H),3.50–3.20(m,5H),2.97–2.64(m,3H),2.19–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.65–8.54(m,1H),7.95(s,1H),7.88–7.78(m,1H),7.76–7.60(m,2H),7.58–7.50(m ,1H),7.50–7.12(m,3H),6.82(d,1H),6.56(dd,1H),4.99–4.88(m,1H),4.45–4.32(m,2H),4.18–4.03(m ,2H),3.95–3.77(m,1H),3.50–3.20(m,5H),2.97–2.64(m,3H),2.19–2.07(m,1H).
实施例187：化合物187的制备
Example 187: Preparation of Compound 187
化合物187以化合物187a为原料，参照实施例147的合成方法得到。Compound 187 was obtained by referring to the synthesis method of Example 147 using compound 187a as a raw material.
1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.83(s,1H),7.75–7.61(m,3H),6.83–6.78(m,1H),6.73–6.67(m,1H),6.59–6.52(m,2H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H)3.88–3.76(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),2.05(s,3H),1.96(s,6H),1.83–1.73(m,1H),1.65–1.55(m,1H),0.93–0.84(m,2H),0.81–0.71(m,2H),0.63–0.57(m,2H),0.54–0.45(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.96(s,1H),7.83(s,1H),7.75–7.61(m,3H),6.83–6.78(m,1H),6.73–6.67(m,1H ),6.59–6.52(m,2H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H)3.88–3.76(m,1H),2.95–2.65( m,3H),2.18–2.08(m,1H),2.05(s,3H),1.96(s,6H),1.83–1.73(m,1H),1.65–1.55(m,1H),0.93–0.84( m,2H),0.81–0.71(m,2H),0.63–0.57(m,2H),0.54–0.45(m,2H).
LCMS m/z＝659.3[M+1]+ LCMS m/z＝659.3[M+1] +
实施例188：化合物188的制备
Example 188: Preparation of Compound 188
第一步：188b的制备Step 1: Preparation of 188b
将2b(2.30g,7.18mmol)溶解在20mL四氢呋喃中，加入4mL水，再加入一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min。向反应液中滴加1mol/L稀盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品(2.0g)。将上述粗品(0.56g)溶于20mL二氯甲烷中，滴加1-氯-N,N,2-三甲基丙烯胺(0.34g，2.54mmol)，室温反应2h后，依次加入188a(0.25g，1.18mmol)和TEA(0.71g，7.02mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝4:1)，得188b(0.45g，收率：79％)。Dissolve 2b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min. Add 1 mol/L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL ethyl acetate, separate the liquids, wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Dissolve the above crude product (0.56g) in 20mL dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (0.34g, 2.54mmol) dropwise, and react at room temperature for 2 hours, then add 188a (0.25 g, 1.18mmol) and TEA (0.71g, 7.02mmol), reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=4:1) to obtain 188b (0.45g, yield: 79%).
第二步：化合物188的制备Step 2: Preparation of Compound 188
将188b(0.45g，0.93mmol)溶于10mL DMF中，依次加入上述粗品中间体1(0.5g)、TEA(0.25g，2.47mmol)、CuI(0.032g，0.17mmol)和PdCl2(PPh3)2(0.058g，0.083mmol)，60℃反应 2h。将反应体系冷却至室温，加入40mL饱和氯化铵溶液，过滤，滤饼用20mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:2)，得化合物188(0.33g，收率：51％)。Dissolve 188b (0.45g, 0.93mmol) in 10mL DMF, and add the above crude intermediate 1 (0.5g), TEA (0.25g, 2.47mmol), CuI (0.032g, 0.17mmol) and PdCl 2 (PPh 3 ) 2 (0.058g, 0.083mmol), reaction at 60°C 2h. Cool the reaction system to room temperature, add 40 mL of saturated ammonium chloride solution, filter, dissolve the filter cake with 20 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate). (v/v)=1:2), compound 188 (0.33g, yield: 51%) was obtained.
1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.40(d,1H),8.06(s,1H),7.82–7.63(m,3H),7.24–7.19(m,1H),7.17–7.09(m,1H),6.80(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.14–4.00(m,2H),3.88–3.74(m,1H),3.14–2.99(m,2H),2.96–2.65(m,5H),2.30–2.00(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.48(s,1H),8.40(d,1H),8.06(s,1H),7.82–7.63(m,3H),7.24–7.19(m,1H), 7.17–7.09(m,1H),6.80(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.14–4.00(m,2H), 3.88–3.74(m,1H),3.14–2.99(m,2H),2.96–2.65(m,5H),2.30–2.00(m,3H).
LCMS m/z＝693.1[M-1]- LCMS m/z＝693.1[M-1] -
实施例189：化合物189的制备
Example 189: Preparation of Compound 189
第一步：189b的制备Step One: Preparation of 189b
将189a(3.00g，12.69mmol)溶于30mL乙醇和10mL水的混合溶剂中，加入还原铁粉(2.12g，37.86mmol)和10mL乙酸，室温反应19h。将反应液用5mol/L氢氧化钠水溶液调pH至7,加入100mL水和100mL乙酸乙酯，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到189b(2.3g，收率：88％)。Dissolve 189a (3.00g, 12.69mmol) in a mixed solvent of 30mL ethanol and 10mL water, add reduced iron powder (2.12g, 37.86mmol) and 10mL acetic acid, and react at room temperature for 19h. Adjust the pH of the reaction solution to 7 with 5 mol/L sodium hydroxide aqueous solution, add 100 mL water and 100 mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum ether/acetic acid Ethyl ester (v/v)=10:1-1:1) to obtain 189b (2.3g, yield: 88%).
LCMS m/z＝206.0[M+1]+ LCMS m/z＝206.0[M+1] +
化合物189以化合物189b为原料，参照实施例174的合成方法得到。Compound 189 was obtained by using compound 189b as a raw material and referring to the synthesis method of Example 174.
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.15–8.07(m,2H),7.83–7.75(m,2H),7.65(d,1H),7.12(t,1H),6.79(d,1H),6.74–6.67(m,1H),6.54(dd,1H),4.97–4.87(m,1H),4.40–4.29(m,2H),4.12–4.01(m,2H),3.88–3.73(m,1H),2.97–2.63(m,3H),2.18–2.02(m,2H),1.94(s,6H),1.00–0.90(m,2H),0.67–0.57(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.71(s,1H),8.15–8.07(m,2H),7.83–7.75(m,2H),7.65(d,1H),7.12(t,1H), 6.79(d,1H),6.74–6.67(m,1H),6.54(dd,1H),4.97–4.87(m,1H),4.40–4.29(m,2H),4.12–4.01(m,2H), 3.88–3.73(m,1H),2.97–2.63(m,3H),2.18–2.02(m,2H),1.94(s,6H),1.00–0.90(m,2H),0.67–0.57(m,2H ).
LCMS m/z＝639.8[M+1]+ LCMS m/z＝639.8[M+1] +
实施例190：化合物190的制备
Example 190: Preparation of Compound 190
第一步：190b的制备Step 1: Preparation of 190b
将190a(1.0g，6.80mmol)溶于20mL DMF中，0℃下加入NBS(1.21g，6.80mmol)，0℃反应0.5h。向反应液中加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到190b(700mg，收率：46％)。Dissolve 190a (1.0g, 6.80mmol) in 20mL DMF, add NBS (1.21g, 6.80mmol) at 0°C, and react at 0°C for 0.5h. Add 50 mL of ethyl acetate and 50 mL of water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1- 1:1), obtaining 190b (700 mg, yield: 46%).
第二步：190c的制备Step 2: Preparation of 190c
将190b(600mg，2.65mmol)溶于5mL三氟乙酸中，加入三乙基硅烷(3.08g，26.49mmol)， 60℃反应16h。将反应体系冷却至室温，减压浓缩，残留物用饱和碳酸氢钠水溶液调pH至9，加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到190c(510mg，收率：91％)。Dissolve 190b (600mg, 2.65mmol) in 5mL trifluoroacetic acid, add triethylsilane (3.08g, 26.49mmol), React at 60°C for 16 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 9 with saturated aqueous sodium bicarbonate solution. 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography. Column separation and purification (petroleum ether/ethyl acetate (v/v)=10:1-1:1) yielded 190c (510 mg, yield: 91%).
化合物190以化合物190c为原料，参考实施例165的合成方法得到。Compound 190 was obtained by using compound 190c as raw material and referring to the synthesis method of Example 165.
1H NMR(400MHz,CDCl3)δ8.42(s,1H),8.00(s,1H),7.88(d,1H),7.80(s,1H),7.72–7.64(m,2H),7.07(d,1H),6.81(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.32(m,2H),4.12–4.02(m,2H),3.87–3.75(m,1H),2.97–2.64(m,7H),2.18–2.07(m,1H),2.06–1.90(m,8H),1.51–1.40(m,1H),0.92–0.80(m,2H),0.45–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.42(s,1H),8.00(s,1H),7.88(d,1H),7.80(s,1H),7.72–7.64(m,2H),7.07( d,1H),6.81(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.32(m,2H),4.12–4.02(m,2H),3.87–3.75( m,1H),2.97–2.64(m,7H),2.18–2.07(m,1H),2.06–1.90(m,8H),1.51–1.40(m,1H),0.92–0.80(m,2H), 0.45–0.37(m,2H).
LCMS m/z＝645.4[M+1]+ LCMS m/z＝645.4[M+1] +
实施例191：化合物191的制备
Example 191: Preparation of Compound 191
化合物191以化合物191a和191A为原料，参照实施例180的合成方法得到。Compound 191 was obtained by referring to the synthesis method of Example 180 using compounds 191a and 191A as raw materials.
1H NMR(400MHz,CDCl3)δ8.76(d,1H),8.62(s,1H),8.51(d,1H),8.18(d,1H),8.06–7.96(m,2H),7.75–7.67(m,2H),7.65–7.59(m,1H),6.84(d,1H),6.60(dd,1H),4.99–4.90(m,1H),4.49–4.40(m,2H),4.28–4.17(m,2H),4.05–3.92(m,1H),2.98–2.65(m,3H),2.20–2.03(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.76(d,1H),8.62(s,1H),8.51(d,1H),8.18(d,1H),8.06–7.96(m,2H),7.75– 7.67(m,2H),7.65–7.59(m,1H),6.84(d,1H),6.60(dd,1H),4.99–4.90(m,1H),4.49–4.40(m,2H),4.28– 4.17(m,2H),4.05–3.92(m,1H),2.98–2.65(m,3H),2.20–2.03(m,1H).
实施例192：化合物192的制备
Example 192: Preparation of Compound 192
第一步：192b的制备Step 1: Preparation of 192b
将192a(3.00g，13.04mmol)溶于30mL甲苯和3mL水的混合溶剂中，加入环丙基硼酸(1.76g，20.49mmol)、三环己基膦(0.89g，3.17mmol)、醋酸钯(0.35g，1.56mmol)和磷酸钾(11.73g，55.26mmol)，氮气保护下100℃反应19h。将反应体系冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到192b(2.05g，收率：82％)。Dissolve 192a (3.00g, 13.04mmol) in a mixed solvent of 30mL toluene and 3mL water, add cyclopropylboronic acid (1.76g, 20.49mmol), tricyclohexylphosphine (0.89g, 3.17mmol), and palladium acetate (0.35 g, 1.56mmol) and potassium phosphate (11.73g, 55.26mmol), reacted at 100°C for 19h under nitrogen protection. The reaction system was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 192b (2.05g, yield: 82%).
第二步：192c的制备Step 2: Preparation of 192c
将192b(1.00g，5.23mmol)溶于10mL乙腈中，加入KI(1.30g，7.83mmol)和CuI(1.49g，7.82mmol)，75℃下加入亚硝基异戊酯(1.10g，9.39mmol)，75℃反应2h。将反应体系冷却至室温，加入80mL乙酸乙酯和100mL水，抽滤，将滤液分液，有机相用无水硫酸钠干燥，减压浓 缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到192c(0.65g，收率：41％)。Dissolve 192b (1.00g, 5.23mmol) in 10mL acetonitrile, add KI (1.30g, 7.83mmol) and CuI (1.49g, 7.82mmol), and add nitrosisoamyl ester (1.10g, 9.39mmol) at 75°C. ), react at 75°C for 2 hours. Cool the reaction system to room temperature, add 80 mL of ethyl acetate and 100 mL of water, filter with suction, separate the filtrate, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1) to obtain 192c (0.65g, yield: 41%).
第三步：192d的制备Step 3: Preparation of 192d
将192c(0.65g，2.15mmol)溶于5mL甲醇和1mL水中，加入一水合氢氧化锂(0.45g，10.72mmol)，室温反应2h。将反应液用1mol/L盐酸调pH至3，加入20mL乙酸乙酯，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1-1:1)，得到192d(0.45g，收率：73％)。Dissolve 192c (0.65g, 2.15mmol) in 5mL methanol and 1mL water, add lithium hydroxide monohydrate (0.45g, 10.72mmol), and react at room temperature for 2h. Adjust the pH of the reaction solution to 3 with 1 mol/L hydrochloric acid, add 20 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) )=5:1-1:1), obtaining 192d (0.45g, yield: 73%).
化合物192以化合物192d为原料，参照实施例44的合成方法得到。Compound 192 was obtained by using compound 192d as a raw material and referring to the synthesis method of Example 44.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.81(s,1H),7.76(s,1H),7.68(d,1H),7.58–7.43(m,3H),7.29(s,1H),7.17(s,1H),6.82(d,1H),6.57(dd,1H),4.99–4.87(m,1H),4.44–4.32(m,2H),4.17–4.03(m,2H),3.90–3.78(m,1H),2.96–2.66(m,3H),2.19–2.06(m,1H),1.89–1.72(m,1H),1.04–0.91(m,2H),0.72–0.52(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,1H),7.81(s,1H),7.76(s,1H),7.68(d,1H),7.58–7.43(m,3H),7.29( s,1H),7.17(s,1H),6.82(d,1H),6.57(dd,1H),4.99–4.87(m,1H),4.44–4.32(m,2H),4.17–4.03(m, 2H),3.90–3.78(m,1H),2.96–2.66(m,3H),2.19–2.06(m,1H),1.89–1.72(m,1H),1.04–0.91(m,2H),0.72– 0.52(m,2H).
实施例193：化合物193的制备
Example 193: Preparation of Compound 193
化合物193以化合物80b为原料，参照实施例81的合成方法得到。Compound 193 was obtained by referring to the synthesis method of Example 81 using compound 80b as raw material.
1H NMR(400MHz,CDCl3)δ8.12(d,1H),7.93(s,1H),7.78–7.64(m,2H),7.62–7.54(m,2H),7.34(s,1H),7.01–6.93(m,2H),6.83(d,1H),6.57(dd,1H),4.98–4.89(m,1H),4.45–4.32(m,2H),4.17–4.06(m,2H),3.93–3.82(m,1H),2.95–2.65(m,3H),2.18–2.05(m,1H),1.90–1.77(m,1H),1.70(s,6H),0.98–0.80(m,2H),0.67–0.57(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.12(d,1H),7.93(s,1H),7.78–7.64(m,2H),7.62–7.54(m,2H),7.34(s,1H), 7.01–6.93(m,2H),6.83(d,1H),6.57(dd,1H),4.98–4.89(m,1H),4.45–4.32(m,2H),4.17–4.06(m,2H), 3.93–3.82(m,1H),2.95–2.65(m,3H),2.18–2.05(m,1H),1.90–1.77(m,1H),1.70(s,6H),0.98–0.80(m,2H ),0.67–0.57(m,2H).
实施例194：化合物194的制备
Example 194: Preparation of Compound 194
化合物194以化合物80b为原料，参照实施例168的合成方法得到。Compound 194 was obtained by referring to the synthesis method of Example 168 using compound 80b as raw material.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.17(s,1H),7.93(s,1H),7.80–7.72(m,1H),7.69(d,1H),7.63–7.55(m,1H),7.38(d,1H),7.26(d,1H),7.08(dd,1H),6.89(d,1H),6.74(dd,1H),5.11–5.02(m,1H),4.48–4.37(m,2H),4.17–4.05(m,2H),4.05–3.92(m,1H),2.98–2.80(m,1H),2.68–2.46(m,2H),2.10–1.90(m,2H),1.03–0.94(m,2H),0.77–0.69(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),10.17(s,1H),7.93(s,1H),7.80–7.72(m,1H),7.69(d,1H), 7.63–7.55(m,1H),7.38(d,1H),7.26(d,1H),7.08(dd,1H),6.89(d,1H),6.74(dd,1H),5.11–5.02(m, 1H),4.48–4.37(m,2H),4.17–4.05(m,2H),4.05–3.92(m,1H),2.98–2.80(m,1H),2.68–2.46(m,2H),2.10– 1.90(m,2H),1.03–0.94(m,2H),0.77–0.69(m,2H).
实施例195：化合物195的制备
Example 195: Preparation of Compound 195
第一步：195b的制备Step One: Preparation of 195b
将吡唑(0.75g，11.02mmol)溶于30mL四氢呋喃中，0℃下加入60％氢化钠(0.29g)，室温反应30min后，加入195a(2.2g，10mmol)，60℃反应16h。将反应体系冷却至室温，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝3:1)，得195b(2.1g，收率：79％)。Dissolve pyrazole (0.75g, 11.02mmol) in 30mL tetrahydrofuran, add 60% sodium hydride (0.29g) at 0°C, react at room temperature for 30 minutes, then add 195a (2.2g, 10mmol), and react at 60°C for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=3:1) to obtain 195b (2.1 g, yield: 79%).
LCMS m/z＝268.1[M+1]+ LCMS m/z＝268.1[M+1] +
第二步：195c的制备Step 2: Preparation of 195c
将195b(2.1g，7.86mmol)溶于50mL乙醇中，加入还原铁粉(2.24g，40mmol)和10mL饱和氯化铵水溶液，回流反应1h。将反应体系冷却至室温，过滤，将滤液减压浓缩，加入80mL乙酸乙酯和50mL纯化水，有机相用无水硫酸钠干燥，减压浓缩，得粗品195c(1.64g)。Dissolve 195b (2.1g, 7.86mmol) in 50mL ethanol, add reduced iron powder (2.24g, 40mmol) and 10mL saturated aqueous ammonium chloride solution, and reflux for 1 hour. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 80 mL of ethyl acetate and 50 mL of purified water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 195c (1.64 g).
化合物195以化合物195c为原料，参考实施例165的合成方法得到。Compound 195 was obtained by using compound 195c as raw material and referring to the synthesis method of Example 165.
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.38(s,1H),8.22(d,1H),7.90–7.80(m,2H),7.77–7.60(m,3H),7.53–7.37(m,2H),6.80(s,1H),6.54(d,1H),6.43(s,1H),5.01–4.86(m,1H),4.44–4.27(m,2H),4.15–3.96(m,2H),3.90–3.70(m,1H),2.96–2.62(m,3H),2.20–2.04(m,1H),1.97(s,6H),1.64–1.47(m,1H),1.02–0.82(m,2H),0.70–0.54(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.69(s,1H),8.38(s,1H),8.22(d,1H),7.90–7.80(m,2H),7.77–7.60(m,3H), 7.53–7.37(m,2H),6.80(s,1H),6.54(d,1H),6.43(s,1H),5.01–4.86(m,1H),4.44–4.27(m,2H),4.15– 3.96(m,2H),3.90–3.70(m,1H),2.96–2.62(m,3H),2.20–2.04(m,1H),1.97(s,6H),1.64–1.47(m,1H), 1.02–0.82(m,2H),0.70–0.54(m,2H).
实施例196：化合物196的制备
Example 196: Preparation of Compound 196
化合物196以化合物196a(CN111138307)为原料，参照实施例164的合成方法得到。Compound 196 was obtained by using compound 196a (CN111138307) as a raw material and referring to the synthesis method of Example 164.
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.30(s,1H),8.27(s,2H),7.91(s,1H),7.86–7.74(m,2H),7.66(d,1H),7.57–7.48(m,1H),7.36–7.29(m,1H),7.29–7.21(m,1H),6.88–6.83(m,1H),6.70(dd,1H),5.12–5.01(m,1H),4.45–4.33(m,2H),4.10–3.97(m,2H),3.95–3.80(m,3H),2.98–2.80(m,1H),2.65–2.52(m,2H),2.10–1.98(m,1H),1.88(s,6H),1.75–1.65(m,1H),0.90–0.75(m,2H),0.65–0.57(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.70(s,1H),8.30(s,1H),8.27(s,2H),7.91(s,1H),7.86–7.74(m,2H), 7.66(d,1H),7.57–7.48(m,1H),7.36–7.29(m,1H),7.29–7.21(m,1H),6.88–6.83(m,1H),6.70(dd,1H), 5.12–5.01(m,1H),4.45–4.33(m,2H),4.10–3.97(m,2H),3.95–3.80(m,3H),2.98–2.80(m,1H),2.65–2.52(m ,2H),2.10–1.98(m,1H),1.88(s,6H),1.75–1.65(m,1H),0.90–0.75(m,2H),0.65–0.57(m,2H).
实施例197：化合物197的制备
Example 197: Preparation of Compound 197
化合物197以化合物197a为原料，参照实施例163的合成方法得到。Compound 197 was obtained by referring to the synthesis method of Example 163 using compound 197a as a raw material.
1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.39(d,1H),8.12(s,1H),7.85–7.77(m,2H),7.68(d,1H),7.58–7.51(m,1H),7.48–7.26(m,3H),7.24–7.07(m,2H),6.84–6.77(m,1H),6.55(dd,1H),4.99–4.88(m,1H),4.43–4.28(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.20–2.05(m,1H),1.97(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.89(s,1H),8.39(d,1H),8.12(s,1H),7.85–7.77(m,2H),7.68(d,1H),7.58– 7.51(m,1H),7.48–7.26(m,3H),7.24–7.07(m,2H),6.84–6.77(m,1H),6.55(dd,1H),4.99–4.88(m,1H), 4.43–4.28(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.20–2.05(m,1H),1.97(s,6H ).
实施例198：化合物198的制备
Example 198: Preparation of Compound 198
第一步：198b的制备Step 1: Preparation of 198b
将198a(3.16g，12.68mmol)溶于30mL乙醇和10mL水的混合溶剂中，加入还原铁粉(2.13g，38.04mmol)和氯化铵(3.39g，63.38mmol)，80℃反应3h。将反应体系冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到198b(1.4g，收率：50％)。Dissolve 198a (3.16g, 12.68mmol) in a mixed solvent of 30mL ethanol and 10mL water, add reduced iron powder (2.13g, 38.04mmol) and ammonium chloride (3.39g, 63.38mmol), and react at 80°C for 3 hours. The reaction system was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 198b (1.4g, yield: 50%).
化合物198以化合物198b为原料，参照实施例192的合成方法得到。Compound 198 was obtained by referring to the synthesis method of Example 192 using compound 198b as raw material.
1H NMR(400MHz,CDCl3)δ8.00(br.s,1H),7.86–7.78(m,2H),7.74–7.60(m,2H),7.57–7.51(m,1H),7.39–7.32(m,1H),7.28–7.23(m,1H),7.01(d,1H),6.86–6.80(m,1H),6.58(dd,1H),5.00–4.87(m,1H),4.47–4.35(m,2H),4.18–4.07(m,2H),3.95–3.80(m,1H),2.97–2.68(m,3H),2.20–2.05(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.00(br.s,1H),7.86–7.78(m,2H),7.74–7.60(m,2H),7.57–7.51(m,1H),7.39–7.32 (m,1H),7.28–7.23(m,1H),7.01(d,1H),6.86–6.80(m,1H),6.58(dd,1H),5.00–4.87(m,1H),4.47–4.35 (m,2H),4.18–4.07(m,2H),3.95–3.80(m,1H),2.97–2.68(m,3H),2.20–2.05(m,1H).
实施例199：化合物199的制备
Example 199: Preparation of Compound 199
化合物199以化合物199a为原料，参照实施例198的合成方法得到。Compound 199 was obtained by using compound 199a as a raw material and referring to the synthesis method of Example 198.
1H NMR(400MHz,CDCl3)δ8.78–8.72(m,1H),8.29–8.21(m,1H),8.05–7.46(m,8H),7.43 –7.32(m,1H),6.88–6.80(m,2H),6.64–6.55(m,1H),4.99–4.87(m,1H),4.49–4.36(m,2H),4.23–4.10(m,2H),3.99–3.85(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.78–8.72(m,1H),8.29–8.21(m,1H),8.05–7.46(m,8H),7.43 –7.32(m,1H),6.88–6.80(m,2H),6.64–6.55(m,1H),4.99–4.87(m,1H),4.49–4.36(m,2H),4.23–4.10(m, 2H),3.99–3.85(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H).
实施例200：化合物200的制备
Example 200: Preparation of Compound 200
化合物200以化合物80b为原料，参照实施例159的合成方法得到。Compound 200 was obtained by referring to the synthesis method of Example 159 using compound 80b as raw material.
1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.96(s,1H),7.82(s,1H),7.75(s,1H),7.67(d,1H),7.01(s,2H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.96–2.62(m,3H),2.20–2.06(m,1H),1.95(s,6H),1.88–1.74(m,1H),1.06–0.94(m,2H),0.72–0.60(m,2H) 1 H NMR (400MHz, CDCl 3 ) δ8.08(s,1H),7.96(s,1H),7.82(s,1H),7.75(s,1H),7.67(d,1H),7.01(s, 2H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.88–3.75( m,1H),2.96–2.62(m,3H),2.20–2.06(m,1H),1.95(s,6H),1.88–1.74(m,1H),1.06–0.94(m,2H),0.72– 0.60(m,2H)
实施例201：化合物201的制备
Example 201: Preparation of Compound 201
第一步：201b的制备Step One: Preparation of 201b
氮气氛围下将201a(0.5g，1.39mmol)(合成方法见WO2017036968)、3-哌啶甲酸甲酯(0.24g，1.68mmol)、CuI(0.082g，0.43mmol)、L-脯氨酸(0.19g，1.65mmol)和碳酸钾(0.39g，2.82mmol)加入到10mL DMSO中，70℃反应18h。将反应体系冷却到室温，加入到50mL水中，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到201b(0.1g，收率：19％)。Under a nitrogen atmosphere, 201a (0.5g, 1.39mmol) (see WO2017036968 for synthesis method), 3-piperidinecarboxylic acid methyl ester (0.24g, 1.68mmol), CuI (0.082g, 0.43mmol), L-proline (0.19 g, 1.65mmol) and potassium carbonate (0.39g, 2.82mmol) were added to 10mL DMSO and reacted at 70°C for 18h. The reaction system was cooled to room temperature, added to 50 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was Separate and purify by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain 201b (0.1g, yield: 19%).
LCMS m/z＝375.4[M+1]+ LCMS m/z＝375.4[M+1] +
第二步：201c的制备Step Two: Preparation of 201c
将201b(0.1g，0.27mmol)溶于2mL甲醇中，用2mol/L氢氧化钠水溶液调pH至10，室温反应2h。向反应液中加入20mL水，用2mol/L盐酸调pH至3，用乙酸乙酯萃取(30mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得到粗品(0.05g)。将上述粗品(0.05g)溶于2mL DCM中，加入16B(0.022g，0.14mmol)、TCFH(0.059g，0.21mmol)和N-甲基咪唑(0.046g，0.56mmol)，室温反应12h。向反应液中加入50mL二氯甲烷和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:0-3:1)，得到201c(0.04g，收率：57％)。Dissolve 201b (0.1g, 0.27mmol) in 2mL methanol, adjust the pH to 10 with 2mol/L sodium hydroxide aqueous solution, and react at room temperature for 2h. Add 20 mL of water to the reaction solution, adjust the pH to 3 with 2 mol/L hydrochloric acid, extract with ethyl acetate (30 mL × 3), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product (0.05 g). Dissolve the above crude product (0.05g) in 2mL DCM, add 16B (0.022g, 0.14mmol), TCFH (0.059g, 0.21mmol) and N-methylimidazole (0.046g, 0.56mmol), and react at room temperature for 12h. Add 50 mL dichloromethane and 50 mL water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:0- 3:1), obtaining 201c (0.04g, yield: 57%).
LCMS m/z＝501.2[M+1]+ LCMS m/z＝501.2[M+1] +
第三步：201d三氟乙酸盐的制备Step 3: Preparation of 201d trifluoroacetate
将201c(0.04g，0.08mmol)溶解于6mL二氯甲烷中，加入2mL三氟乙酸，室温搅拌1h。将反应体系减压浓缩，得到粗品201d的三氟乙酸盐(0.032g)。Dissolve 201c (0.04g, 0.08mmol) in 6mL dichloromethane, add 2mL trifluoroacetic acid, and stir at room temperature for 1h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 201d (0.032g).
LCMS m/z＝401.5[M+1]+ LCMS m/z＝401.5[M+1] +
第四步：化合物201的制备Step 4: Preparation of Compound 201
将上述粗品201d的三氟乙酸盐(0.032g)溶解于5mL DMSO中，加入DIPEA(0.062g，0.48mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(0.044g，0.16mmol)，90℃反应1.5h。将反应体系冷却至室温，加入到40mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(40mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:二氯甲烷:乙酸乙酯(v/v)＝1:1:0-1:1:1)，得到化合物201(0.005g，收率：5％)。Dissolve the trifluoroacetate salt (0.032g) of the above crude product 201d in 5mL DMSO, add DIPEA (0.062g, 0.48mmol) and 2-(2,6-dioxopiperidin-3-yl)-5- Fluoroisoindoline-1,3-dione (0.044g, 0.16mmol), react at 90°C for 1.5h. The reaction system was cooled to room temperature, added to 40 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (40 mL : dichloromethane: ethyl acetate (v/v)=1:1:0-1:1:1) to obtain compound 201 (0.005g, yield: 5%).
1H NMR(400MHz,CDCl3)δ9.67(s,1H),8.51(d,1H),7.99(s,1H),7.68(d,1H),7.51(dd,1H),7.38–7.26(m,3H),7.10–6.95(m,2H),6.90–6.80(m,1H),6.59(dd,1H),5.00–4.86(m,1H),4.54–4.37(m,2H),4.10–3.90(m,3H),3.77–3.65(m,1H),3.54–3.37(m,1H),3.28–3.15(m,1H),3.10–2.65(m,5H),2.22–1.76(m,5H),1.62–1.47(m,1H),0.82–0.44(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ9.67(s,1H),8.51(d,1H),7.99(s,1H),7.68(d,1H),7.51(dd,1H),7.38–7.26( m,3H),7.10–6.95(m,2H),6.90–6.80(m,1H),6.59(dd,1H),5.00–4.86(m,1H),4.54–4.37(m,2H),4.10– 3.90(m,3H),3.77–3.65(m,1H),3.54–3.37(m,1H),3.28–3.15(m,1H),3.10–2.65(m,5H),2.22–1.76(m,5H ),1.62–1.47(m,1H),0.82–0.44(m,4H).
LCMS m/z＝657.2[M+1]+ LCMS m/z＝657.2[M+1] +
实施例202：化合物202的制备
Example 202: Preparation of Compound 202
第一步：202a的制备Step One: Preparation of 202a
将146f(0.3g，0.95mmol)、1-溴代环丁烷甲酸乙酯(0.2g，0.97mmol)和碳酸铯(0.62g，1.9mmol)溶于10mL乙腈中，50℃反应16h。将反应体系冷却到室温，过滤，将滤液加入到50mL水中，用乙酸乙酯萃取(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用prep-TLC制备分离纯化(石油醚:乙酸乙酯(v/v)＝5:1)，得到202a(70mg，收率：17％)。Dissolve 146f (0.3g, 0.95mmol), ethyl 1-bromocyclobutanecarboxylate (0.2g, 0.97mmol) and cesium carbonate (0.62g, 1.9mmol) in 10 mL acetonitrile, and react at 50°C for 16 hours. Cool the reaction system to room temperature, filter, add the filtrate to 50 mL of water, extract with ethyl acetate (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by prep-TLC (petroleum ether: acetic acid Ethyl ester (v/v) = 5:1) to obtain 202a (70 mg, yield: 17%).
LCMS m/z＝444.2[M+1]+ LCMS m/z＝444.2[M+1] +
第二步：202b的制备Step 2: Preparation of 202b
将202a(0.07g，0.158mmol)溶于2mL甲醇中，用2mol/L氢氧化钠水溶液调pH至10，室温反应2h。将反应体系加入到50mL水中，用2mol/L盐酸调pH至2，用乙酸乙酯萃取(50mL×3)，无水硫酸钠干燥，减压浓缩，得到粗品(50mg)。将上述粗品(50mg)溶于2mL DCM中，加入3-氯-4-氨基三氟甲苯(0.023g，0.12mmol)、TCFH(0.051g，0.182mmol)和N-甲基咪唑(0.039g，0.475mmol)，室温反应12h。向反应液中加入50mL二氯甲烷和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:0-3:1)，得到202b(0.04g，收率：56％)。Dissolve 202a (0.07g, 0.158mmol) in 2mL methanol, adjust the pH to 10 with 2mol/L sodium hydroxide aqueous solution, and react at room temperature for 2h. The reaction system was added to 50 mL of water, adjusted to pH 2 with 2 mol/L hydrochloric acid, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product (50 mg). Dissolve the above crude product (50mg) in 2mL DCM, add 3-chloro-4-aminotrifluorotoluene (0.023g, 0.12mmol), TCFH (0.051g, 0.182mmol) and N-methylimidazole (0.039g, 0.475 mmol), react at room temperature for 12 h. Add 50 mL dichloromethane and 50 mL water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:0- 3:1), obtaining 202b (0.04g, yield: 56%).
第三步：202c三氟乙酸盐的制备Step 3: Preparation of 202c trifluoroacetate
将202b(0.04g，0.067mmol)溶于6mL二氯甲烷中，加入2mL三氟乙酸，室温反应1h。 将反应体系减压浓缩，得到粗品202c三氟乙酸盐(0.033g)。Dissolve 202b (0.04g, 0.067mmol) in 6mL dichloromethane, add 2mL trifluoroacetic acid, and react at room temperature for 1 hour. The reaction system was concentrated under reduced pressure to obtain crude product 202c trifluoroacetate (0.033g).
第四步：化合物202的制备Step 4: Preparation of Compound 202
将上述粗品202c三氟乙酸盐(0.033g)溶于5mL DMSO中，加入DIPEA(0.053g，0.41mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(0.044g，0.16mmol)，90℃反应1.5h。将反应体系冷却至室温，加入到40mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(40mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:二氯甲烷:乙酸乙酯(v/v)＝1:1:0-1:1:1)，得到化合物202(5mg，收率：4％)。Dissolve the above crude product 202c trifluoroacetate (0.033g) in 5mL DMSO, add DIPEA (0.053g, 0.41mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro Isoindoline-1,3-dione (0.044g, 0.16mmol), react at 90°C for 1.5h. The reaction system was cooled to room temperature, added to 40 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (40 mL : dichloromethane: ethyl acetate (v/v)=1:1:0-1:1:1) to obtain compound 202 (5 mg, yield: 4%).
生物测试例Biological test examples
1.抑制22RV1细胞增殖实验1. Inhibition of 22RV1 cell proliferation experiment
前列腺癌细胞22RV1购置于ATCC，细胞培养基为RPMI 1640+10％FBS，培养于37℃,5％CO2孵箱中。第一天收集处于指数生长期的细胞，用1％css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板，使细胞为2000个/孔，孵育过夜。第二天加入不同浓度的化合物，置于孵箱中培养继续孵育7天。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7573)操作说明，每孔加入50μL预先融化并平衡到室温的CellTiter-Glo试剂，用微孔板震荡器混匀2分钟，于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。结果按照式(1)处理，计算出化合物各个浓度的抑制率，并使用origin9.2软件，采用DoseResp函数计算化合物抑制率为50％的IC50值。其中RLUcompound为药物处理组的读数，RLUcontrol为DMSO溶剂对照组的平均值。
Inhibition％＝[1-RLUcompound/RLUcontrol]×100％   式(1)Prostate cancer cell 22RV1 was purchased from ATCC. The cell culture medium was RPMI 1640+10% FBS and cultured in a 37°C, 5% CO 2 incubator. Collect cells in the exponential growth phase on the first day, use 1% css-FBS phenol red-free medium, adjust the cell suspension to the corresponding concentration and plate it to 2000 cells/well, and incubate overnight. The next day, compounds of different concentrations were added, placed in an incubator, and incubated for another 7 days. After the incubation, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 50 μL of CellTiter-Glo reagent that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and leave it at room temperature for 10 minutes. The fluorescence signal value was then measured using a microplate reader (PHERAstar FSX). The results are processed according to formula (1), the inhibition rate of each concentration of the compound is calculated, and the IC 50 value of the compound's inhibition rate of 50% is calculated using the origin9.2 software and the DoseResp function. Among them, RLU compound is the reading of the drug treatment group, and RLU control is the average value of the DMSO solvent control group.
Inhibition%=[1-RLU compound /RLU control ]×100% Formula (1)
抑制22RV1细胞增殖的IC50值结果见表1。The IC 50 value results for inhibiting 22RV1 cell proliferation are shown in Table 1.
表1本发明化合物抑制22RV1细胞的IC50值

Table 1 IC50 value of compounds of the present invention inhibiting 22RV1 cells

结论：本发明化合物，例如实施例化合物对前列腺细胞22RV1具有良好的抑制作用，具体的如表1所示。 Conclusion: The compounds of the present invention, such as the example compounds, have good inhibitory effects on prostate cells 22RV1, as shown in Table 1.
2.22RV1细胞中AR剪切突变体7(AR-V7)的降解实验2.2 Degradation experiment of AR splicing mutant 7 (AR-V7) in RV1 cells
前列腺癌细胞22RV1购置于ATCC，细胞培养基为1640+10％FBS，培养于37℃，5％CO2孵箱中。第一天收集处于指数生长期的细胞，用1％css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板，6孔板每孔1mL，细胞数量为300000个/孔。次日加入含待测化合物的1％css-FBS无酚红培养基，其中一个孔加入0.2％DMSO的1％css-FBS无酚红培养基作为DMSO溶媒对照，6孔板培养于37℃,5％CO2孵箱中。24或48小时后，胰酶消化，收集细胞于1.5mL离心管，向每孔加入15μL RIPA裂解液(含1X蛋白酶抑制剂混合物(Protease Inhibitor cocktail))，于冰上裂解15分钟后，12000g，4℃，离心10分钟。收集上清蛋白样品，用BCA法进行蛋白定量。使用全自动蛋白质表达定量分析检测AR-V7，实验过程如下，将待测蛋白浓度稀释至2mg/mL。取4μL稀释后的蛋白样品加入1μL 5×Master Mix(试剂盒提供)，将配制好的样品放在95℃变性5分钟，放在冰上待用。使用Antibody Diluent II(试剂盒提供)稀释一抗，一抗为AR V7(CST,19672S)与β-actin(CST,3700)，稀释比例分别为1:10和1:500。二抗为1:1混合羊抗小鼠和羊抗兔二抗，显色液为1:1混合的Lumino-S和Peroxide。按照试剂盒说明书将配制好的试剂依次加入检测板内，上机检测。Western条带处理使用全自动蛋白质表达定量分析软件“Compass for SW”根据信号值自动模拟western条带。根据式(2)计算不同药物浓度下，AR-V7(2)相对于溶媒对照的降解率。其中AR-V7compound为给药组AR-V7相对峰面积，AR-V7solvent为溶媒对照组AR-V7相对峰面积。
AR-V7％＝(1-AR-V7compound/AR-V7solvent)×100％   式(2)Prostate cancer cell 22RV1 was purchased from ATCC, the cell culture medium was 1640+10% FBS, and cultured in a 37°C, 5% CO2 incubator. Cells in the exponential growth phase were collected on the first day, and the cell suspension was adjusted to the corresponding concentration using 1% css-FBS phenol red-free medium and plated, with 1 mL per well of a 6-well plate, and the number of cells was 300,000 cells/well. The next day, 1% css-FBS phenol red-free medium containing the compound to be tested was added, and 0.2% DMSO of 1% css-FBS phenol red-free medium was added to one well as a DMSO solvent control. The 6-well plate was cultured at 37°C. 5% CO 2 incubator. After 24 or 48 hours, trypsinize, collect the cells in a 1.5mL centrifuge tube, add 15μL RIPA lysis solution (containing 1X protease inhibitor cocktail (Protease Inhibitor cocktail)) to each well, lyse on ice for 15 minutes, 12000g, Centrifuge at 4°C for 10 minutes. Supernatant protein samples were collected and protein quantified using BCA method. Use fully automated protein expression quantitative analysis to detect AR-V7. The experimental process is as follows. Dilute the protein concentration to be tested to 2 mg/mL. Take 4 μL of the diluted protein sample and add 1 μL of 5×Master Mix (provided by the kit). Denature the prepared sample at 95°C for 5 minutes and put it on ice until use. Use Antibody Diluent II (provided in the kit) to dilute the primary antibodies. The primary antibodies are AR V7 (CST, 19672S) and β-actin (CST, 3700). The dilution ratios are 1:10 and 1:500 respectively. The secondary antibody was a 1:1 mixture of goat anti-mouse and goat anti-rabbit secondary antibodies, and the chromogenic solution was a 1:1 mixture of Lumino-S and Peroxide. According to the instructions of the kit, add the prepared reagents to the detection plate in sequence, and run the test on the machine. Western band processing uses the fully automatic protein expression quantitative analysis software "Compass for SW" to automatically simulate western bands based on signal values. Calculate the degradation rate of AR-V7(2) relative to the vehicle control under different drug concentrations according to formula (2). Among them, AR-V7 compound is the relative peak area of AR-V7 in the administration group, and AR-V7 solvent is the relative peak area of AR-V7 in the vehicle control group.
AR-V7%=(1-AR-V7 compound /AR-V7 solvent )×100% Formula (2)
DC50计算：按照式(2)处理，使用Graphpad软件计算并采用log(inhibitor)vs.response–Variable slope(four parameters)函数分析AR-V7降解率为50％时的化合物浓度DC50值。DC 50 calculation: According to formula (2), use Graphpad software to calculate and use the log (inhibitor) vs. response–Variable slope (four parameters) function to analyze the DC 50 value of the compound concentration when the AR-V7 degradation rate is 50%.
表2 48小时降解AR-V7的DC50
Table 2 DC 50 for degradation of AR-V7 in 48 hours
结论：本发明化合物，例如实施例化合物对前列腺细胞22RV1中AR-V7具有良好的降解作用。Conclusion: The compounds of the present invention, such as the example compounds, have a good degradation effect on AR-V7 in prostate cells 22RV1.
3.大鼠药代动力学测试3. Rat pharmacokinetic test
实验目的：本试验通过单剂量静脉和灌胃给予受试物于SD大鼠，测定大鼠血浆中受试物的浓度，评价受试物在大鼠体内药代特征。Purpose of the experiment: In this experiment, the test substance was administered to SD rats through a single dose intravenously and intragastrically, to measure the concentration of the test substance in rat plasma, and to evaluate the pharmacokinetic characteristics of the test substance in rats.
试验动物：雄性SD大鼠，200～250g，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。Test animals: male SD rats, 200-250g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验方法：试验当天，6只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药 后4h给食。Test method: On the day of the test, 6 SD rats were randomly divided into groups according to body weight. Do not eat or drink for 12 to 14 hours one day before administration. Feed 4 hours later.
表3
table 3
*剂量以游离碱计。*Dosage is based on free base.
取样：于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。Sampling: Before and after administration, 0.1 mL of blood was taken from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.
IV&PO组采集血浆时间点：0,5min,15min,30min,1,2,4,6,8,24h。The plasma collection time points in the IV&PO group were: 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, and 24h.
分析检测前，所有样品存于-60℃。用LC-MS/MS对样品进行定量分析。Before analysis and detection, all samples were stored at -60°C. Samples were quantitatively analyzed using LC-MS/MS.
表4本发明化合物在大鼠血浆中药代动力学参数

Table 4 Pharmacokinetic parameters of the compounds of the present invention in rat plasma

*注：i.g.(灌胃)给予化合物；N/A：未测*Note: Compounds administered i.g. (gavage); N/A: Not tested
结论：运用本发明化合物，例如实施例化合物在大鼠体内具有较好的的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in rats.
4.小鼠药代动力学测试4. Mouse pharmacokinetic test
4.1试验动物：雄性ICR小鼠，25～30g，6只/化合物。购于成都达硕实验动物有限公司。4.1 Test animals: male ICR mice, 25-30g, 6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
4.2试验设计：试验当天，6只ICR小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。4.2 Experimental design: On the day of the experiment, 6 ICR mice were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表5.给药信息
Table 5. Dosing information
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
口服(灌胃)给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,7,24h。分析检测前，所有样品存于-60℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 0.1 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Before analysis and detection, all samples were stored at -60°C and quantitatively analyzed using LC-MS/MS.
结论：运用本发明化合物，例如实施例化合物在小鼠体内具有较好的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in mice.
5.比格犬药代动力学测试5. Beagle dog pharmacokinetics test
试验动物：雄性比格犬，8～10kg左右，6只/化合物，购于北京玛斯生物技术有限公司。Experimental animals: male beagles, about 8-10kg, 6/compound, purchased from Beijing Mas Biotechnology Co., Ltd.
试验方法：试验当天，6只比格犬按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。Test method: On the day of the test, 6 beagle dogs were randomly divided into groups according to body weight. No food and water for 14 to 18 hours one day before administration, and food 4 hours after administration.
表6.给药信息
Table 6. Dosing Information
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
口服(灌胃)给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后通过颈静脉或四肢静脉取血1mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24,48h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1 mL of blood was taken from the jugular vein or limb veins and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24, 48h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS.
结论：运用本发明化合物，例如实施例化合物在犬体内具有较好的口服吸收。 Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in dogs.
6.猴药代动力学测试6. Monkey pharmacokinetic test
试验动物：雄性食蟹猴，3～5kg，3～6年龄，4只/化合物。购于苏州西山生物技术有限公司。Test animals: male cynomolgus monkeys, 3 to 5 kg, 3 to 6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
试验方法：试验当天，4只猴按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。Test method: On the day of the test, 4 monkeys were randomly divided into groups according to body weight. No food and water for 14 to 18 hours one day before administration, and food 4 hours after administration.
表7.给药信息
Table 7. Dosing information
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
口服(灌胃)给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1.0 mL of blood was taken from the veins of the limbs and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, and 24h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS.
结论：运用本发明化合物，例如实施例化合物在猴体内具有较好的口服吸收。Conclusion: The compounds of the present invention, such as the compounds in the examples, have better oral absorption in monkeys.
7.hERG钾离子通道作用测试7.hERG potassium ion channel function test
实验平台：电生理手动膜片钳系统Experimental platform: electrophysiology manual patch clamp system
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after infusion of the electrode liquid is about 2-5MΩ. The glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier. Clamp voltage and data recording were controlled and recorded via computer using pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz. After obtaining the whole-cell recording, the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ≥ 2).
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Inhibition％＝[1–(I/Io)]×100％Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50mV) at different compound concentrations was calculated using the following formula:
Inhibition%＝[1–(I/Io)]×100%
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。Among them, Inhibition% represents the inhibition percentage of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。 Among them, X is the Log value of the detected concentration of the test product, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages respectively.
结论：本发明化合物，例如实施例化合物对hERG钾通道电流没有明显的抑制作用。Conclusion: The compounds of the present invention, such as the examples, have no obvious inhibitory effect on hERG potassium channel current.
8.肝微粒体稳定性测试8. Liver Microsome Stability Test
本实验采用人、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。This experiment uses five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substance.
在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC-MS/ The MS method detects the concentration of the test substance in the sample, and calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL int (mic) and the liver intrinsic clearance rate CL int(Liver) .
结论：本发明化合物，例如实施例化合物具有良好的肝微粒体稳定性。Conclusion: The compounds of the present invention, such as the example compounds, have good liver microsome stability.
9.CYP450酶抑制测试9.CYP450 enzyme inhibition test
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC 50 value, and evaluate the effect of the test substance on each Inhibitory potential of CYP enzyme isoforms.
结论：本发明化合物，例如实施例化合物对人肝微粒体细胞色素P450的5种同工酶没有明显的抑制作用。Conclusion: The compounds of the present invention, such as the examples, have no obvious inhibitory effect on the five isoenzymes of human liver microsomal cytochrome P450.
10.Caco2渗透性测试10.Caco2 permeability test
试验使用单层Caco-2细胞，在96孔Transwell板中采用三平行孵育。将含有本发明化合物(2μM)或对照化合物地高辛(10μM)、纳多洛尔(2μM)和美托洛尔(2μM)的转运缓冲溶液(HBSS，10mM HEPES，pH 7.4±0.05)加入顶端侧或基底侧的给药端孔中。对应接收端孔中加入含DMSO的转运缓冲溶液。在37±1℃条件下孵育2小时后，取出细胞板并从顶端和底端各取出适量样品至新的96孔板中。随后加入含内标的乙腈沉淀蛋白。使用LC MS/MS分析样品并测定本发明化合物和对照化合物的浓度。浓度数据用于计算从单层细胞顶端侧向基底侧、以及基底侧向顶端转运的表观渗透系数，从而计算外排率。用荧光黄的渗漏评价孵育2小时后单层细胞的完整性。The assay uses a monolayer of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the invention (2μM) or the control compounds digoxin (10μM), nadolol (2μM) and metoprolol (2μM) was added to the apical side or in the administration port hole on the basal side. Add DMSO-containing transport buffer solution to the corresponding receiving port hole. After incubating for 2 hours at 37±1°C, remove the cell plate and take appropriate amounts of samples from the top and bottom ends into a new 96-well plate. Acetonitrile containing internal standard was then added to precipitate the protein. Samples were analyzed using LC MS/MS and the concentrations of compounds of the invention and control compounds were determined. Concentration data were used to calculate apparent permeability coefficients for transport from the apical side to the basal side, and from the basal side to the apical side of the cell monolayer, and thus the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.
结论：本发明化合物，例如实施例化合物具有一定的Caco2渗透性。Conclusion: The compounds of the present invention, such as the example compounds, have certain Caco2 permeability.
11.本发明化合物对小鼠22RV1皮下移植瘤模型生长的抑制实验11. Experiment on the inhibition of the growth of the 22RV1 subcutaneous transplanted tumor model in mice by the compounds of the present invention
细胞培养：22RV1细胞(来源于ATCC)体外培养，培养条件为添加10％胎牛血清以及含10μg/mL重组胰岛素的培养基，37℃，5％CO2。一周常规传代2次。当细胞维持在指数增长期时，收取细胞，计数，接种。Cell culture: 22RV1 cells (derived from ATCC) were cultured in vitro. The culture conditions were medium supplemented with 10% fetal calf serum and 10 μg/mL recombinant insulin at 37°C and 5% CO 2 . Passaging was performed twice a week. When the cells are maintained in the exponential growth phase, cells are harvested, counted, and plated.
动物：BALB/c nude小鼠，雄性，4-6周龄，体重14-20克。由北京维通利华实验动物技术有限公司提供。Animals: BALB/c nude mice, male, 4-6 weeks old, weighing 14-20 grams. Provided by Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
肿瘤接种：实验小鼠于右侧背部皮下接种5×106 22RV1细胞，细胞重悬在PBS与基质胶(1:1)中，定期观察肿瘤生长情况，待肿瘤生长至平均体积为80mm3时进行去势：用异氟烷麻醉小鼠，手术阉割通过阴囊中线切口进行，允许双侧进入，暴露每个睾丸后，用5-0vicryl缝线结扎精索，然后切除睾丸，然后分别用5-0Vicyryl缝合阴囊和皮肤，术后需继续观察动物至完全苏醒。去势后，肿瘤可能缩小(肿瘤退化)，当平均肿瘤体积重新生长到100mm3左右时开始分组和治疗， 分组当天为Day 0。Tumor inoculation: Experimental mice were subcutaneously inoculated with 5×10 6 22RV1 cells on the right back. The cells were resuspended in PBS and Matrigel (1:1). Tumor growth was observed regularly until the tumor grew to an average volume of 80 mm 3 Perform castration: Anesthetize mice with isoflurane, and surgical castration is performed through a midline incision in the scrotum, allowing bilateral access. After exposing each testicle, the spermatic cord is ligated with 5-0 vicryl sutures, and then the testicles are removed, and then each testicle is ligated with 5-0 vicryl sutures. 0Vicyryl sutures the scrotum and skin, and the animal needs to continue to be observed after surgery until it fully wakes up. After castration, the tumor may shrink (tumor regression), and grouping and treatment can begin when the average tumor volume re-grows to about 100 mm. The day of grouping is Day 0.
给药：本发明化合物按照一定给药剂量，口服给药(PO)，每天一次给药(QD)，每组10只小鼠，所有组持续给药28天。Administration: The compound of the present invention was administered orally (PO) and once a day (QD) according to a certain dosage. There were 10 mice in each group, and all groups were administered continuously for 28 days.
实验观察和结束：每周3次测量小鼠体重以及肿瘤测量。给药28天后结束实验，安乐死所有小鼠。肿瘤体积计算公式：肿瘤体积(mm3)＝1/2×(a×b2)(其中a表示长径，b表示短径)，原始数据由天平和游标卡尺测量。Experimental observation and conclusion: The mouse body weight and tumor measurement were measured three times a week. The experiment was terminated 28 days after administration, and all mice were euthanized. Tumor volume calculation formula: tumor volume (mm 3 ) = 1/2 × (a × b 2 ) (where a represents the long diameter and b represents the short diameter), and the original data were measured by a balance and a vernier caliper.
结论：本发明化合物，例如实施例化合物对小鼠22RV1皮下移植瘤模型生长有一定的抑制作用。Conclusion: The compounds of the present invention, such as the example compounds, have a certain inhibitory effect on the growth of the mouse 22RV1 subcutaneous transplanted tumor model.
12. 1.HEK293细胞增殖实验12. 1.HEK293 cell proliferation experiment
人胚肾293细胞HEK293购置于ATCC，完全培养基为EMEM+10％FBS，培养于37℃,5％CO2孵箱中。收集处于指数生长期的细胞，用完全培养基将细胞悬液调整为相应浓度并铺板，使细胞为1000个/孔，体积为每孔180μL。次日加入20μL不同浓度的化合物，置于孵箱中继续孵育培养7天。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7573)操作说明，每孔加入50μL预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2分钟，于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。化学发光读数使用Graphpad Prim 8.0软件，采用使用四参数非线性回归模型绘制S型浓度曲线并计算IC50值。结果按照式(3)处理，计算出化合物各个浓度的增殖率Growth％，并使用Graphpad Prim 8.0软件，计算增殖率为50％时化合物的浓度IC50值。其中RLUcompound为药物处理组的读数，RLUcontrol为溶剂对照组的平均值。
Growth％＝RLUcompound/RLUcontrol×100％    式(3)Human embryonic kidney 293 cells HEK293 were purchased from ATCC. The complete culture medium was EMEM+10% FBS and cultured in a 37°C, 5% CO 2 incubator. Collect cells in the exponential growth phase, adjust the cell suspension to the corresponding concentration with complete culture medium and plate it so that the number of cells is 1000/well and the volume is 180 μL per well. The next day, 20 μL of compounds of different concentrations were added and placed in an incubator to continue incubation for 7 days. After the culture, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 50 μL of CTG solution that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and leave it at room temperature for 10 minutes before using. The fluorescence signal value was measured with a microplate reader (PHERAstar FSX). Chemiluminescence readings were performed using Graphpad Prim 8.0 software, using a four-parameter nonlinear regression model to draw a S-shaped concentration curve and calculate the IC 50 value. The results were processed according to formula (3), the growth rate of each concentration of the compound was calculated, and the IC 50 value of the concentration of the compound when the growth rate was 50% was calculated using Graphpad Prim 8.0 software. Among them, RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group.
Growth%=RLU compound /RLU control ×100% Formula (3)
抑制HEK293细胞增殖的IC50值结果见表8。The IC 50 value results for inhibiting HEK293 cell proliferation are shown in Table 8.
表8本发明化合物抑制HEK293细胞的IC50值
Table 8 IC50 value of compounds of the present invention inhibiting HEK293 cells
结论：本发明化合物，例如实施例化合物对人胚肾293细胞HEK293具有较弱的抑制作用，具体的如表8所示。 Conclusion: The compounds of the present invention, such as the example compounds, have weak inhibitory effects on human embryonic kidney 293 cells HEK293, as shown in Table 8.

Claims (14)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物，
    B-L-K   (I)；    A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
    BLK(I);
    L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
    每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, - NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -NR L (CH 2 ) q C(＝O)-, -(CH 2 ) q -C( =O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH＝CH-, -Si( R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)(R L )-, - S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from halogen, OH, CN, Substitution of NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl substituted by base;
    q各自独立的选自0、1、2、3、4、5或6；q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
    RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
    每个-Cy-各自独立地选自键或者任选取代的如下基团之一：4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Each -Cy- is independently selected from a bond or one of the optionally substituted groups: 4-8 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterospirocyclic ring Heterobridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl group, Benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, heteroaryl, The heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatoms are selected from S, they are optionally substituted by 1 or 2 =O;
    RL2各自独立地选自氘、F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene -OC 1-4 alkyl, -OC 1-4 alkylene -OC 3-10 carbocyclyl, -C 1-4 alkylene- OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene- OC 3-10 carbocyclyl, -OC 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -4 to 10 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, Substituted with hydroxyl-substituted C 1-4 alkyl and C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    B选自 B is selected from
    B1选自C5-20碳环基或4-20元杂环基，所述B1任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl. The B 1 is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
    B2选自C5-20碳环基或4-20元杂环基，所述B2任选被1至4个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl. The B 2 is optionally substituted by 1 to 4 R b2 . The heterocyclyl contains 1 to 4 selected from O, Heteroatoms of S and N;
    V选自 V is selected from
    W选自O或S；W is selected from O or S;
    Y1、Y2、Y3各自独立地选自键、O、S、NRb5a、C(＝S)、C(＝O)、CONRb5a、NRb5aCO；Y 1 , Y 2 , Y 3 are each independently selected from bonds, O, S, NR b5a , C(=S), C(=O), CONR b5a , NR b5a CO;
    P1、P2各自独立地选自 P 1 and P 2 are each independently selected from
    v2各自独立地选自0、1、2、3或4；v 2 are each independently selected from 0, 1, 2, 3 or 4;
    v1各自独立地选自0、1或2；v 1 are each independently selected from 0, 1 or 2;
    Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-ORb22、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、-C1-4亚烷基-C3-6环烷基、-C1-4亚烷基-OH、-C1-4亚烷基-O-C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group, C 1-4 alkylthio group, -(CH 2 ) n -R b22 , -OR b22 , -N(R b21 ) 2 , -C(=O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S(＝O) 2 N( R b21 ) 2 , -NR b21 C(=O)R b22 , -NR b21 S(=O) 2 R b22 , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl Or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optional Substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene Substituted by -OH, -C 1-4 alkylene -OC 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy substituents;
    Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基或4-8元杂环基，所述的烷基、烷氧基、环烷基、烯基、炔基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C3-6环烷基氧基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-8 yuan Heterocyclyl, the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2. Substituted with substituents of CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, and C 1-4 alkoxy, as described The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
    n各自独立的选自0、1、2、3或4；n is independently selected from 0, 1, 2, 3 or 4;
    Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4烷基、-C(＝O)N(C1-4烷基)2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-8环烷基、C6-10芳基、5-10元杂芳基、4-10元杂环基、-C1-4亚烷基-4至10元杂环基，所述的亚烷基、CH2、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基氧基、卤素取代的C3-6环烷基、卤素取代的C3-6环烷基氧基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , - C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group , C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C 1-4 alkylene-4 to 10 membered heterocyclyl, so The above-mentioned alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3-6 cycloalkyloxy, 5-6 yuan Substituted with a substituent of a heteroaryl group or a 4-8 membered heterocyclyl group, the heteroaryl group or heterocyclyl group containing 1 to 4 heteroatoms selected from O, S, and N;
    Rb3、Rb4、Rb6、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 , R b4 , R b6 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio The base, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen Substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with substituents, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    或Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    作为选择，Rb3与Rb5a、Rb1与Rb5a直接连接形成环S，环S选自4至9元含氮杂环基，环S任选被1至4个选自Rs的取代基所取代； Alternatively, R b3 and R b5a , R b1 and R b5a are directly connected to form ring S. Ring S is selected from 4 to 9-membered nitrogen-containing heterocyclic groups. Ring S is optionally substituted by 1 to 4 substituents selected from Rs . replaced;
    Rs各自独立的选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基、5-6元杂芳基或3至8杂环基，所述的烷基、烷氧基、环烷基、杂芳基或者杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 ring Alkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally 1 to 4 selected from F, Substituted with Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group or heteroaryl group contains 1 to 4 selected from Heteroatoms of O, S, and N;
    Rb5a选自H或Rb5；R b5a is selected from H or R b5 ;
    Rb5选自OH、NH2、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3 -6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl Or the heteroaryl group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkyl Substituents of oxygen group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    X各自独立的选自NH、O或S；X is each independently selected from NH, O or S;
    m1各自独立的选自0、1、2或3；m1 is each independently selected from 0, 1, 2 or 3;
    m2各自独立的选自0、1、2或3；m2 is independently selected from 0, 1, 2 or 3;
    Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-6环烷基或4-10元杂环基，所述的环烷基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    Rb24各自独立的选自C1-4烷氧基、C3-6环烷基氧基、C3-6环烷基或4-10元杂环基，所述的烷氧基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 are each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl. The alkoxy, cycloalkyl The base, cycloalkyloxy group and heterocyclyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S , N heteroatoms;
    K选自K1、K2、K3、K4；K is selected from K1, K2, K3, K4;
    K1选自 K1 is selected from
    K2选自 K2 is selected from
    K3选自 K3 is selected from
    K4选自 K4 is selected from
    Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或3-12元杂环，所述的杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 3-12 membered heterocycles, The heterocyclic ring is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
    Rq选自H或C1-6烷基；R q is selected from H or C 1-6 alkyl;
    A选自C3-10碳环、C6-10芳环、3-10元杂环或5-10元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；A is selected from C 3-10 carbocyclic ring, C 6-10 aromatic ring, 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring. The heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or heteroatoms of N;
    F各自独立地选自C3-20碳环、C6-20芳环、3-20元杂环或5-20元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；Each F is independently selected from C 3-20 carbocyclic ring, C 6-20 aromatic ring, 3-20 membered heterocyclic ring or 5-20 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from Heteroatom of O, S or N;
    Rk2各自独立地选自键、-CO-、-SO2-、-SO-或-C(Rk3)2-；R k2 is each independently selected from bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
    Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, Rk7a , the alkyl, alkoxy or cycloalkyl is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted by CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
    Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
    Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, = Substituted with O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S or N heteroatoms;
    或者两个Rk3和与二者直接相连的碳原子或环骨架共同形成C3-8碳环或3-8元杂环，两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-8碳环或3-8元杂环，所述碳环或杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atoms or ring skeleton directly connected to them together form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring, and the two R k1 and the carbon atoms or ring skeleton directly connected to them form a C 3-8 carbocyclic ring or 3-8 membered heterocycle. Forming a C 3-8 carbocyclic ring or a 3-8 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
    Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子； R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl The base or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；M 1 is selected from the group consisting of bonds, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
    M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkyl, cycloalkyl Or the heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, so The heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    M3选自-NH-或-O-；M 3 is selected from -NH- or -O-;
    Rk10选自C1-6烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 ring Substituted by alkyl substituents;
    Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
    Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents substituted;
    Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；R k14 is selected from 5-6 membered heteroaryl groups, and the heteroaryl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkane Substituted by a substituent of a halogen-substituted C 1-4 alkyl group, a hydroxyl-substituted C 1-4 alkyl group, a C 1-4 alkoxy group or a C 3-6 cycloalkyl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
    G选自C6-10芳环或5-10元杂芳环，所述的芳环或者杂芳环任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳环含有1至4个选自N、O或S的杂原子；G is selected from C 6-10 aromatic ring or 5-10 membered heteroaromatic ring, and the aromatic ring or heteroaromatic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3. Substituents of CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl Substituted, the heteroaromatic ring contains 1 to 4 heteroatoms selected from N, O or S;
    n1、n2、n3各自独立的选自0、1、2或3；n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
    p1或p2各自独立的选自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    B选自 B is selected from
    v2各自独立地选自1、2、3或4；v 2 are each independently selected from 1, 2, 3 or 4;
    v1各自独立地选自0、1或2；v 1 are each independently selected from 0, 1 or 2;
    v3选自0、1、2或3；v 3 is selected from 0, 1, 2 or 3;
    v4选自0、1、2或3；v 4 is selected from 0, 1, 2 or 3;
    z选自0、1、2或3；z is selected from 0, 1, 2 or 3;
    W选自O或S；W is selected from O or S;
    的定义与B1相同； The definition of is the same as B 1 ;
    B1、B4各自独立的选自C6-14碳环基或5-14元杂环基，所述B1、B4任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl. The B 1 and B 4 are optionally substituted by 1 to 4 R b1 , and the heterocyclic The base contains 1 to 4 heteroatoms selected from O, S, and N;
    B2选自C5-10碳环基、5-10元杂环基或B5，所述B2任选被1至4个Rb2取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 . The B 2 is optionally substituted by 1 to 4 R b2 , and the heterocyclyl contains 1 to 4 optional R b 2 . Heteroatoms from O, S, N;
    B3选自C6-14碳环基或4-14元杂环基，所述B3任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl. The B 3 is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
    B5选自C12-18三并环、12至18元杂三并环、噻吩基、呋喃基、噻唑基、噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、苯基、苯并C4-6碳环、苯并4至6元杂环、吡唑并C4-6碳环、吡唑并4至6元杂环、三氮唑并C4-6碳环、三氮唑并4至6元杂环、咪唑并C4-6碳环、咪唑并4至6元杂环、噻吩并C4-6碳环、噻吩并4至6元杂环、呋喃并C4-6碳环、呋喃并4至6元杂环、4-7元含氮杂单环烷基、4-10元含氮杂并环烷基、5-12元含氮杂螺环烷基、7-10元含氮杂桥环烷基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基，所述B5任选被1至4个Rb2取代，所述的杂环、杂单环烷基、杂并环烷基、杂螺环烷基、杂桥环烷基含有1至4个选自O、S、N的杂原子；B 5 is selected from C 12-18 tricyclic ring, 12 to 18 membered heterotricyclic ring, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine base, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, triazolo C 4- 6 carbocyclic ring, triazolo 4 to 6 membered heterocyclic ring, imidazo C 4 to 6 carbocyclic ring, imidazo 4 to 6 membered heterocyclic ring, thieno C 4 to 6 carbocyclic ring, thieno 4 to 6 membered heterocyclic ring , furo C 4-6 carbocyclic ring, furo 4- to 6-membered heterocycle, 4-7-membered nitrogen-containing heteromonocycloalkyl, 4-10-membered nitrogen-containing heterocycloalkyl, 5-12-membered nitrogen-containing heterocyclic alkyl Spirocycloalkyl, 7-10-membered nitrogen-containing hetero-bridged cycloalkyl, 3-7-membered monocyclic alkyl, 4-10-membered cycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged ring Alkyl, the B 5 is optionally substituted by 1 to 4 R b2 , the heterocycle, heteromonocycloalkyl, heterocycloalkyl, heterospirocycloalkyl, heterobridged cycloalkyl contains 1 to 4 4 heteroatoms selected from O, S, and N;
    Rb5选自OH、NH2、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10 芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3 -6 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally replaced by 1 to 4 Each is selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the heteroaryl or The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
    Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4炔基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的炔基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl, cycloalkyl, aryl , heteroaryl or heterocyclic group optionally substituted by 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano The heteroaromatic _ _ The base or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C2-4炔基、C3-12环烷基、C6-10芳基、5-10元杂芳基或4-12元杂环基，所述的烷基、烷氧基、烷硫基、炔基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group or The heterocyclic group is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and cyano. Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, the heteroaryl or heterocyclic The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
    或Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子。Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The ring, heteroaryl or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, N.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    B选自 B is selected from
    环S选自5元、6元或7元含有1或2个氮原子的环，环S任选被1至4个Rs取代；Ring S is selected from a 5-membered, 6-membered or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;
    Rs各自独立的选自F、Cl、Br、I、OH、NH2、-NHC1-4烷基、-N(C1-4烷基)2、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基，所述的烷基、烷氧基或者环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基或C1-4烷氧基的取代基所取代；R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy group, C 3-6 cycloalkyl group, the alkyl group, alkoxy group or cycloalkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , Substituted by CN, C 1-4 alkyl or C 1-4 alkoxy substituents;
    B1、B4各自独立的选自苯基、萘基、C6-12碳环基、5-10元杂芳基、5-10元杂环基、C10-14三环碳环基、12至14元三环杂环基，所述B1、B4任选被1至4个Rb1所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;
    B2选自C6-10芳基、5-7元杂环基、5-10元杂芳基或5-10元杂并环、5-10元杂桥环，所述B2任选被1至4个Rb2取代，所述的杂芳基、杂环基、杂并环、杂桥环含有1至4个选自O、S、N的杂原子；B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5-10 membered heterobridged ring, and the B 2 is optionally replaced by 1 to 4 R b2 substituted, and the heteroaryl, heterocyclyl, heterocyclic, and heterobridged rings contain 1 to 4 heteroatoms selected from O, S, and N;
    B3选自5-12元杂芳基、C6-7碳环基、C6-10并碳环基、C6-12螺碳环基、C7-12桥碳环基、4-7元单环杂环基、7-14元杂并环、7-14元杂螺环，所述B3任选被1至4个Rb1所取代，所述的杂芳基、杂环基、杂并环、杂螺环含有1至4个选自O、S、N的杂原子；B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 1-membered monocyclic heterocyclyl, 7-14-membered heterocyclic, 7-14-membered heterospirocyclic, the B 3 is optionally substituted by 1 to 4 R b1 , the heteroaryl, heterocyclyl, Heterocyclic rings and heterospirocyclic rings contain 1 to 4 heteroatoms selected from O, S, and N;
    Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4烷基、-C(＝O)N(C1-4烷基)2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-8环烷基、C6-10芳基、5至6元杂芳基、4至8元杂环基、-C1-4亚烷基-4至8元杂环基，所述的亚烷基、CH2、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、NH2、-NHC1-4烷基、-N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基氧基、卤素取代的C3-6环烷基、卤素取代的C3-6环烷基氧基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , - C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group , C 3-8 cycloalkyl, C 6-10 aryl, 5 to 6-membered heteroaryl, 4 to 8-membered heterocyclyl, -C 1-4 alkylene-4 to 8-membered heterocyclyl, so The above-mentioned alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3 -6 cycloalkyloxy, 5-6-membered heteroaryl or 4-8-membered heterocyclyl substituents, the heteroaryl or heterocyclic group containing 1 to 4 selected from O, S, N heteroatoms;
    Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 炔基、C3-6环烷基、C5-10桥环烷基、C5-12螺环烷基、C4-12并环烷基、C6-10芳基、5-6元杂芳基、4-8元杂环基、5-10元杂桥环、5-12元杂螺环、5-12元杂并环，所述的炔基、环烷基、芳基、杂芳基、杂环基、杂桥环、杂螺环或杂并环任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 Alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered hetero Aryl, 4-8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocyclic, 5-12-membered heterocyclic, the alkynyl, cycloalkyl, aryl, heteroaryl base, heterocyclyl, heterobridged ring, heterospirocycle or heterocyclic ring optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen Substitution of C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with a base, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    Rb3、Rb4、Rb7各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C2-4炔基、C3-6环烷基、C5-10桥环烷基、C5-12螺环烷基、C4-12并环烷基、C6-10芳基、5-6元杂芳基、4-8元杂环基、5-10元杂桥环、5-12元杂螺环、5-12元杂并环，所述的烷基、烷氧基、烷硫基、炔基、环烷基、芳基、杂芳基、杂环基、杂桥环、杂螺环或杂并环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基、杂环基、杂桥环、杂螺环或杂并环含有1至4个选自O、S、N的杂原子；R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5 -10-membered hetero-bridged ring, 5-12-membered heterospiro ring, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group , Heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospirocycle or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
    或Rb3、Rb4与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-6环烷基或4-8元杂环基，所述的环烷基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    Rb24各自独立的选自C1-4烷氧基、C3-6环烷基氧基、C3-6环烷基或4-8元杂环基，所述的烷氧基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the alkoxy, cycloalkyl The base, cycloalkyloxy group and heterocyclyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S , N heteroatoms;
    任选地，B选自时，Rb3、Rb4不能同时选自H。Optionally, B is selected from When , R b3 and R b4 cannot be selected from H at the same time.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、 -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2 -Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2 -Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1 -Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3 -Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1 -Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
    Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 )q-NR L C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝ O)-, -C(＝O)-(CH 2 ) q -NR L -, -CH＝CH-, -(C≡C) q -or bond, the -CH 2 -, -CH＝CH - C 1-4 alkyl optionally substituted by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen, Substituted with substituents of hydroxyl-substituted C 1-4 alkyl and cyano-substituted C 1-4 alkyl;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或者任选取代的如下基团之一：4-7元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；q各自独立的选自0、1、2、3或4；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or optionally substituted following groups: 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, Heteroaryl, heteromonocycle, heteroparacycle, heterospirocycle or heterobridged ring contain 1 to 4 heteroatoms selected from O, S, N. When the heteroatoms are selected from S, they are optionally replaced by 1 or 2 =O substitution; q is each independently selected from 0, 1, 2, 3 or 4;
    RL各自独立的选自H或C1-6烷基；R L are each independently selected from H or C 1-6 alkyl;
    K2选自 K2 is selected from
    K3选自 K3 is selected from
    A选自C3-8碳环、苯环、4-7元杂环或5-6元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；A is selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring or 5-6 membered heteroaromatic ring. The heterocyclic ring or heteroaromatic ring contains 1 to 4 heterocyclic rings selected from O, S or N. atom;
    F各自独立地选自C3-7单环碳环、C4-10并环碳环、C5-12螺环碳环、C5-10桥环碳环、4-7元杂单环、4-10元杂并环、8-15元杂三并环、5-12元杂螺环、5-10元杂桥环、C6-14芳基、5-10元杂芳基、所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个选自O、S或N的杂原子；F is each independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 paracyclic carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 8-15 membered heterotriacyclic ring, 5-12 membered heterospirocyclic ring, 5-10 membered heterobridged ring, C 6-14 aryl group, 5-10 membered heteroaryl group, The heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
    表示环选自芳香环或非芳香环； Indicates that the ring is selected from aromatic rings or non-aromatic rings;
    E各自独立地选自C3-10碳环、苯环、4-12元杂环、5-12元杂芳环，所述杂环或杂芳环含有1至4个选自O、S或N的杂原子；Each E is independently selected from C 3-10 carbocyclic ring, benzene ring, 4-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or N heteroatoms;
    Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-CO-、-NRqCO-、-CONRq-或4-7元杂环，所述的杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 4-7 membered heterocycles, wherein The heterocyclic ring is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
    Rq选自H或C1-4烷基；R q is selected from H or C 1-4 alkyl;
    Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH或NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkyl Oxygen group, the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH 2 ;
    或者两个Rk3和与二者直接相连的碳原子或环骨架共同形成C3-6碳环或3-7元杂环，两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环或3-7元杂环，所述碳环或杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atoms or ring skeleton directly connected to them together form a C 3-6 carbocyclic ring or 3-7 membered heterocyclic ring, and the two R k1 and the carbon atoms or ring skeleton directly connected to them together form Forming a C 3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;
    Rk4各自独立的选自H、OH、NH2、CF3、CN或C1-4烷基；R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;
    Rk5各自独立地选自C(CH3)2、CO、CH2、SO2、 R k5 are each independently selected from C(CH 3 ) 2 , CO, CH 2 , SO 2 ,
    Rk6各自独立地选自CO、CH、SO、SO2、CH2或N；R k6 is each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
    Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、NRk7a；R k7 are each independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
    Rk8各自独立地选自C、N或CH； Rk8 is each independently selected from C, N or CH;
    Rk9各自独立地选自键、C(CH3)2、CO、CH2、CH2CH2或SO2；R k9 are each independently selected from keys, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
    Rka选自O、S或NH；R ka is selected from O, S or NH;
    Rk7a选自H、C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷 基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl alkyl The base and heterocycloalkyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2 Substituted with -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
    Rk14选自 R k14 selected from
    p1选自0、1、2或3；p1 is selected from 0, 1, 2 or 3;
    p2选自0、1、2或3。p2 is selected from 0, 1, 2 or 3.
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或者任选取代的如下基团之一：4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: 4-7-membered nitrogen-containing heteromonocycle, 4-10-membered nitrogen-containing heterocyclic ring, 5-12-membered Nitrogen-containing heterospirocycle, 7-10 membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group base, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, substituted by 1 to 4 R L2 , the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S , optionally replaced by 1 or 2 =O;
    RL各自独立的选自H或C1-4烷基；R L are each independently selected from H or C 1-4 alkyl;
    K1选自 K1 is selected from
    K4选自 K4 is selected from
    Q选自键、C(＝O)；Q is selected from bond, C(=O);
    Q1选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 Q1 is selected from bonds, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 ),
    Q2选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；Q2 is selected from bonds, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);
    E、A各自独立地选自苯环、吡啶环、哒嗪环、吡嗪环、嘧啶环、吡咯环、吡唑环、咪唑环、噻唑环、呋喃环、噻吩环或噁唑环；E and A are each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;
    F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮基、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、吡啶并吡唑基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、 其左侧与L直接连接；F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridimidazolyl, benzo Imidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl , benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, Imidazopyridazinyl, pyrazopyridinyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidine Pyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrazolyl, pyridazinopyridazinyl, pyridazinopyridazinyl, pyrazinopyrazinyl, Its left side is directly connected to L;
    Rka选自O、S或NH；R ka is selected from O, S or NH;
    Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
    Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基，所述甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基任选被1至4个选自F、Cl、Br、I、OH、NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy methyl, ethoxy or isopropoxy, the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted by 1 to 4 selected from F, Cl, Br, Substituted by I, OH, NH 2 substituents;
    Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代； Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl Substituted with substituents of C 3-6 cycloalkyl group;
    p1或p2各自独立的选自0、1或2。p1 or p2 are each independently selected from 0, 1 or 2.
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    RL选自H、甲基或乙基；R L is selected from H, methyl or ethyl;
    q各自独立的选自0、1或2；q is independently selected from 0, 1 or 2;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡啶酮、三嗪基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶、吡唑并吡啶基、吡唑并吡嗪基、吡唑并嘧啶基、苯并噻吩基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、苯并吡咯基、三氮唑并吡啶基、三氮唑并嘧啶基、三氮唑并哒嗪基、三氮唑并吡嗪基、三氮唑并噻唑基、三氮唑并噁唑基、三氮唑并吡唑基、三氮唑并吡咯基、三氮唑并咪唑基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基 并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrole base, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridyl , pyrazolopyrazinyl, pyrazopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl , triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyridinyl, triazolothiazolyl, triazoloxazolyl, triazolo Pyrazolyl, triazolopyrrolyl, triazoloimidazolyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl Butylcyclobutyl, cyclobutylcyclohexyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl , cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidine cyclobutyl, cyclobutyl Pyrrolidinyl, cyclobutylpiperidyl, cyclopentaazetidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexyl pyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazepine cyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, piperidinolazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiro Azetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexyl Spiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl Aldyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, by 1 to 4 R L2 ;
    RL2各自独立的选自氘、F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、羟基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子； R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene-OC 1-2 alkyl, -OC 1-2 alkylene-OC 3-6 carbocyclyl , -C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl , the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylene group, carbocyclic group or heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, COOH, CN , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl Substituted with oxygen, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    B1、B4各自独立的选自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、3-异喹啉酮基、喹唑啉基、3,4-二氢-1H-苯并吡喃基、1,2,3,4-四氢喹啉基、苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、 所述的B1、B4任选被1至4个Rb1所取代；B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, 3- Isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-tetrahydroquinolyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, The B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;
    B2选自取代或未取代的如下基团之一：苯基、萘基、吡唑基、咪唑基、三氮唑基、噻唑基、噁唑基、异噁唑基、噻吩基、吡啶基、苯并吡咯基、苯并咪唑基、苯并吡唑基、苯并噻唑基、吡唑并四氢吡咯基、3-哒嗪酮基、2-吡啶酮基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、 或B5，当被取代时，被1至4个Rb2取代；B 2 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl , benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4 -Tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, or B5 , when substituted, by 1 to 4 R b2 ;
    B5选自 所述B5任选被1至4个Rb2取代；B 5 selected from The B 5 is optionally substituted by 1 to 4 R b2 ;
    B3选自取代或未取代的如下基团之一：苯基、萘基、 苯并吡啶基、苯并噻吩基、苯并呋喃基、噻吩基、呋喃基、吡咯基，当被取代时，被1至4个Rb1取代；B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, Benzopyridyl, benzothienyl, benzofuryl, thienyl, furyl, pyrrolyl, when substituted, are substituted by 1 to 4 R b1 ;
    Rb1各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、 环丁基螺环己基、环戊基螺环己基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、乙炔基、-CH2-CN、-CH2OH、-CH2OMe、-CH2-环丙基、甲氧基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、咪唑基、吡唑基、三氮唑基、四氮唑基的取代基所取代；R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3 , -C(= O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O)(CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy base, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidine base, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, morpholine, pyrrolidinyl, piperidinyl, azetidinylspirocyclohexyl, cyclopropyl Spirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, Cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, When substituted, 1 to 4 are selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, iso Propyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidine Substituted with substituents such as piperidinyl, morpholinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl;
    Rb2各自独立的选自H、F、Cl、Br、I、＝O、OH、NH2、NH(CH3)、N(CH3)2、CN、NO2、COOH、-C(＝O)NH2或者任选取代的如下基团之一：-CH2OCH2CH3、甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基，当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、NHCH3、N(CH3)2、甲基、乙基、异丙基、甲氧基、乙氧基、吡唑基、吗啉基、氧杂环己基、环丙基、环丁基、环丙基氧基、 的取代基所取代；R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CN, NO 2 , COOH, -C(=O )NH 2 or optionally substituted one of the following groups: -CH 2 OCH 2 CH 3 , methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, Ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl , thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxanyl, cyclopropyl, cyclobutyl, cyclopropyloxy, Substituted by substituents;
    Rb3、Rb4各自独立的选自H、OH、NH2或者任选取代的如下基团之一：甲基、乙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基，当被取代时，被1至4个选自氘、F、Cl、Br、I、OH、NH2、CN、CF3、CHF2、甲基、甲氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、吡唑基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基的取代基所取代；R b3 and R b4 are each independently selected from H, OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, cyclobutylspirocyclobutyl, when When substituted, it is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl Substituents of base, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, cyclobutylspirocyclobutyl replaced;
    或Rb3、Rb4与其相连接的碳原子共同形成任选取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、环丁基螺环丁基，当被取代时，被1至4个选自氘、F、Cl、Br、I、OH、NH2、N(CH3)、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or R b3 , R b4 and the carbon atoms to which they are connected together form one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazyl Aldyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, are selected from 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , N(CH 3 ), CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C Substituted with 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 optional Heteroatoms from O, S, N;
    Rb5选自OH、NH2、甲基、乙基、丙基、异丙基、-(CH2)n-环丙基、-(CH2)n-环丁基、-(CH2)n-环戊基、-(CH2)n-环己基、苯基、吡啶基，所述的-CH2-、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5 is selected from OH, NH 2 , methyl, ethyl, propyl, isopropyl, -(CH 2 ) n -cyclopropyl, -(CH 2 ) n -cyclobutyl, -(CH 2 ) n -Cyclopentyl, -(CH 2 ) n -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, C 1 -4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl Substituted with a substituent, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    n各自独立的选自0、1；n is independently selected from 0 and 1;
    Rb6选自F、Cl、Br、I、OH、NH2、CN、NO2、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24或者取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环 丁基、氧杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、吡啶基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or substituted or unsubstituted as follows One of the groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetamine Butyl, oxetanyl, pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclo Propylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutyl Cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropyl Spirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspirocyclohexyl Propylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl , cyclopentaazetidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, Azetidinyl azetidinyl, azetidinyl pyrrolidinyl, azetidinyl piperidinyl, pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidinyl, Pyrrolidopiperidinyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidine base, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropyrolidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl base, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl ,pyrrolidinylspiropyrrolidyl,pyrrolidinylspiropiperidinyl,piperidinylspiroazetidinyl,piperidinylspiropiperidinyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano -4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
    Rb7选自H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24或者取代或未取代的如下基团之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, pyrrolidinyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, cyclopropyl cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, Cyclopent-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocycle Hexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl Azetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentyl Azetidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetamine Butyl azetidinyl, azetidinopyrrolidyl, azetidinopiperidinyl, pyrrolidinaazetidinyl, pyrrolidinopyrrolidyl, pyrrolidinyl Piperidinyl, piperidylazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, ring Butylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropyrolidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiroazetidinyl Hexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropyrolidinyl, pyrrolidinylspiroazetidinyl, pyrrolidine Spiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano -4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;
    X各自独立的选自NH、O或S；X is each independently selected from NH, O or S;
    m2各自独立的选自0、1或2；m2 is each independently selected from 0, 1 or 2;
    Rb23各自独立的选自乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉，所述的乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；R b23 is each independently selected from vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl , oxolanyl, oxanyl, piperidine or morpholine, the vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, azepanyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents ;
    Rb24各自独立的选自甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丙基氧基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉，所述的甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌啶或吗啉任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；R b24 is each independently selected from methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclopropyloxy, cyclobutyl, cyclopentyl, cyclohexyl, azetidine base, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the methoxy, ethoxy, propoxy group , isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl , oxanyl, piperidine or morpholine optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen Substituted with C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents;
    K选自表K-1所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-1.
  7. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 6 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
    RL2各自独立地选自氘、F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙 氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、-OCHF2、-OCF3、甲基、甲氧基、＝O、羟甲基、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代； RL2 is each independently selected from deuterium, F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the optionally substituted following groups: methyl, Ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethyl Oxygen, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine , -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, - OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, is selected from 1 to 4 Substitution of F, CHF 2 , CF 3 , -OCHF 2 , -OCF 3 , methyl, methoxy, =O, hydroxymethyl, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 substituted by base;
    B选自表B-1或表B-2所示的结构片段之一；B is selected from one of the structural fragments shown in Table B-1 or Table B-2;
    K选自表K-2所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-2.
  8. 根据权利要求7所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 7 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自键或表L-1或表L-2所示的结构片段之一，其中基团左侧与B连接。L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2, in which the left side of the group is connected to B.
  9. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一。The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one.
  10. 一种药物组合物，包括权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中包含1-1500mg权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical an acceptable carrier, preferably, the pharmaceutical composition contains 1-1500 mg of the compound according to any one of claims 1-9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or eutectics.
  11. 根据权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与AR或AR剪切突变体活性或表达量相关疾病的药物中的应用。The compound according to any one of claims 1 to 9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation of treatment with AR or AR Application of splice mutants in drugs for diseases related to activity or expression levels.
  12. 根据权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解AR或AR剪切突变体相关疾病的药物中的应用。The compound according to any one of claims 1 to 9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used for the preparation of treatment and inhibition or degradation Applications in medicines for diseases related to AR or AR splice mutants.
  13. 根据权利要求11或12所述的应用，其中，所述的疾病选自前列腺癌。Use according to claim 11 or 12, wherein said disease is selected from prostate cancer.
  14. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选AR或AR剪切突变体活性或表达量相关疾病。 A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-9 or its stereoisomers, deuterated products, solvates, or protoplasts. Drugs, metabolites, pharmaceutically acceptable salts or co-crystals, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably a disease related to the activity or expression of AR or AR splicing mutants.
PCT/CN2023/091444 2022-04-29 2023-04-28 Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical application thereof WO2023208165A1 (en)

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